J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

5625 Med Genet 1991; 28: 562-574

ABSTRACTS OF THE MEETING OF THE CLINICAL GENETICS SOCIETY HELD ON 20 TO 22 MARCH 1991 AT BELFAST CITY HOSPITAL

Linkage analysis of familial Malignant hyperthermia (MH) is an the presence of a missense mutation, expansile osteolysis inherited skeletal muscle condition, in previously defined as pathological, in A E HUGHES, A SHEARMAN, which the administration ofinhalational the affected boy but not in his brother. R J BARR, R A B MOLLAN, anaesthetics is potentially fatal. Sus- Further PCR sequencing and ASO N C NEVIN ceptibility to MH can be accurately hybridisation has shown that this Departments of Medical Genetics predicted by the in vitro stimulation of mutation is not present in either of the and Orthopaedic Surgery, The Queen's muscle biopsy material. Irish and mother's CYP21B genes, but is present University of Belfast, Belfast City North American family studies have in both of her CYP21A pseudogenes, Hospital, Belfast BT9 7AB. implicated chromosome 19; the suggesting a gene conversion-like ryanodine receptor and the hormone origin. Analysis of sequence flanking Familial expansile osteolysis (FEO) is a sensitive lipase loci on 19q12-13.2 have this mutation in the mother's pseudo- genetic bone dysplasia that is apparently both been suggested as candidates for genes and the affected boy's CYP21B unique to a large family in Northern the MH locus. We have undertaken gene suggests a conversion event Ireland. The disorder is inherited as an genetic linkage analysis of three involving between 1 and 390 bp. These autosomal dominant trait which results generation families previously investi- results represent the first report of a de in focal failure of osteoblast/osteoclast gated at the Leeds MH Unit, which is novo point mutation causing 21- homeostasis. Those affected develop the UK reference centre. Members of hydroxylase deficiency and the most progressive expansile and lytic lesions these families were typed unequivocally direct evidence to date for gene in the limb bones, causing pain, using the European diagnostic criteria conversion in man. deformity, and pathological fracture. for MH. Three of these families all Life expectancy is not reduced, but yielded positive lod scores for chromo- there is no satisfactory treatment for some 19 markers (Zmax=2-1 at 0= the disorder. Linkage analysis has been 0-05 for Mfd9 (D19S47) and Zmax= carried out using DNA from 61 1-2 at 0=0-20 for Mfd5 (APOC2)). Evidence for linkage of hereditary members of this pedigree, of whom 35 There is therefore no evidence for hydronephrosis to the MHC on http://jmg.bmj.com/ are affected. Several candidate genes genetic heterogeneity as yet, but a chromosome 6p for known bone related proteins have wider range ofclinical and geographical L IZQUIERDO*, P PARAMOt, been excluded from causing FEO. material must be examined before M PORTEOUS4, J M CONNOR* These include the genes for collagen routine DNA presymptomatic testing *Duncan Guthrie Institute of Medical type I (COLlAl and COL1A2 on can be considered valid. Genetics, Glasgow; fHospital chromosomes 17 and 7, respectively), Universitario San Carlos, Madrid, osteonectin (chromosome 5), bone Spain; tDepartment ofHuman Genetics,

alkaline phosphatase (chromosome 1), A de novo point mutation causing Newcastle. on September 24, 2021 by guest. Protected copyright. and the met and rbi oncogenes human 21-hydroxylase deficiency: (chromosomes 7 and 13, respectively) evidence for a gene conversion event Prospective study of first degree which are associated with osteo- S COLLIER, P J SINNOTT, R HARRIS, relatives of affected patients with pelvi- sarcoma. In addition, approximately T STRACHAN ureteric junction obstruction has 70% of the genome has been excluded. University Department of Medical suggested that at least one third to one Genetics, St Mary's Hospital, half of pelviureteric junction obstruc- Manchester M13 0_JH. tion is familial (Atwell, 1985). Twenty- Genetic linkage analysis in human two families have now been described malignant hyperthermia We have previously reported a family with hereditary pelviureteric junction A D STEWART' , J L HALL*, with 21-hydroxylase deficiency with obstruction in a pattern consistent with G R TAYLOR", R F MUELLER*, two HLA identical brothers, one autosomal dominant inheritance but F R ELLISt, P J HALSALLt, affected and the other unaffected. with variable expression and incomplete P HOPKINSt, S P BALLf, Short and long range restriction penetrance (MIM 143000). Two point H R DORKINS§ mapping has shown that the boys both linkage analysis was undertaken in four 'Yorkshire Regional DNA Laboratory, carry a deletion of the CYP2lB gene on families with hereditary pelviureteric University of Leeds; fUniversity their paternally derived haplotype. We junction obstruction using the MHC Department ofAnaesthesia, Leeds; have therefore used a PCR sequencing locus as a test marker and was carried tWashington Singer Laboratories, method to compare the single mater- out with the linkage program LIPED 3 University of Exeter; 5University nally derived CYP21B gene in both using a disease allele frequency of College, Oxford. subjects. Sequence analysis has shown 0-001 and with penetrance of 100% and J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

Clinical Genetics Society 563

90%. Family 1 is a three generation larger American family gaveamaximum provide evidence of an important family in which well documented uni- lod score of 2 59 at 0=0-15. This genetic component in the aetiology of lateral hydronephrosis was present in lower score was partially because of the schizophrenia. However, the mode of the grandfather, the father, and two structure of the family and the number transmission (or modes of transmission sons (Paramo et al, 1991). Families 2 of subjects in whom clinical status was if schizophrenia is a group of different and 3 were reported by Buscemi et al unknown. The combined lod score of disorders) remains obscure. The search (1985). Family 2 is a two generation 8-61 and 0=0-15 would suggest, as for linkage markers in schizophrenia is family with two sibs affected. Family 3 previous work has indicated, that the X therefore premised, not on any certain includes a woman with two marriages linked HMSN locus is more likely to evidence for the existence of genes of and two affected and two unaffected be well distal to Xpl 1.22 and probably major effect but on the fact that there is offspring from each healthy partner. between the centromere and Xql 3. no compelling evidence against their Family 4 was reported by Sengar et al existence. Despite the interest sur- (1979) and is a two generation family Localisation of the gene for X linked rounding a recent provocative report, with five out of 13 sibs affected. anophthalmos to Xq27-28 new data from a study in Wales, Maximum lod scores were 3 9 at a together with a reanalysis of published of0-05 with full C A GRAHAM, R M REDMOND, recombination fraction N C NEVIN data from elsewhere, strongly suggest penetrance and 4-26 at a recombination Regional Genetics Centre, Belfast City that there is no susceptibility gene for fraction of 0-0 with a penetrance of Hospital, Belfast BT9 7AB. schizophrenia on chromosome 5q. 90%. These data provide evidence for Similarly, previous claims of genetic assignment of the locus (or loci) for Anophthalmos is a very rare condition linkage between marker genes and a hereditary pelviureteric junction ob- characterised by developmental failure putative schizophrenia gene elsewhere struction to chromosome 6p. The of the optic vesicle and cup. Th- (for example, on the short arm of routine management of patients with majority of cases are the result of new chromosome 6) have been effectively pelviureteric junction obstruction mutations, cytogenetic abnormalities, refuted. Despite this, the increasing should include scanning of relatives or damage during embryonic develop- availability of new DNA markers and and genetic counselling using empiric ment. The prevalence ofthese disorders the production of a virtually complete recurrence riskas these becomedefined. is about 1/100 000. We report on a human genetic linkage map increases Northern Ireland family with seven theviability ofgenetic linkagestrategies. anophthalmic males in two generations. Groups in Europe under the auspices A linkage study of X linked hereditary Male to male transmission has not of the European Science Foundation, motor and sensory neuropathy occurred and this family shows and in the USA coordinated by the (HMSN) with M27, X linked recessive clinical anoph- National Institute of Mental Health, S COCHRANE*, N HAITES*, thalmos. There are four affected males, are currently embarking on large scale K FISCHBECKt, K KELLY*, seven normal males, and three obligate collaborative investigations involving a N FAIRWEATHER*, A JOHNSTON* systematic search throughout the female carriers available for linkage http://jmg.bmj.com/ *Medical Genetics, University of analysis. Multipoint linkage analysis. human genome on a large sample of Aberdeen, Foresterhill, Aberdeen; with Xp markers, Xg, XJl.1, 754, and multiplex families. Therefore, if major tNeurology Department, Hospital of M27,B has excluded the disease from genes do exist, they are likely to be University of Pennsylvania, most of the short arm of the X chromo- discovered within the next five years Philadelphia, USA. some. However, with distal Xq markers but even if genes of 'major effect' do DX13 and factor 8, only one recom- not play a part it is possible that the Previous studies of X linked HMSN binant in 11 males was noted, giving a material being collected can still prove have shown linkage of the disease locus maximum lod score of 1-9 at 0=0 08. useful in detecting genes which make a to loci mapped to the centromeric Multipoint analysis was carried out relatively small contribution. on September 24, 2021 by guest. Protected copyright. regions of Xp and Xq. In a large using the probes p6al, Cx33.2, DX13, Scottish family, Haites et al found and F8 and the LINKMAP program linkage to PGKI (Xql3) and DXYSI from LINKAGE vs 5 04. Two location Schizophrenia in the Afro-Caribbean (Xq2l.31). Fischbeck et al, studying a score peaks were detected, one of 7-7 community: a family study large X linked family from North just proximal to DX13 and one of 7-2 PHILIP SUGARMAN, DAVID CRAUFURD Carolina, showed linkage to the loci just distal to F8. Thus it is likely that Departments of Psychiatry and defined by the probe 58-1 (DXS14 at the anophthalmos gene is localised in Medical Genetics, University of Xpll.21) and p8 (DXSI at Xqll-q13) the Xq27-28 region, distal to Cx33.2 Manchester. both with recombination frequencies of and not between DX13 and F8. 0-05. In an attempt to define more The incidence of schizophrenia in the closely the position of the gene, we Afro-Caribbean community in Britain have studied these two large X linked Molecular genetics and is three to six times higher than for the families with the highly informative, schizophrenia: an update indigenous population. Rates are parti- polymorphic probe M270. In both PETER MCGUFFIN, MICHAEL J OWEN cularly high among younger people families, the number of phase known Department of Psychological Medicine born in this country. The cause of this females with informative meioses was and Institute ofMedical Genetics, apparent epidemic is not known, but it greatly increased compared with the University of Wales College ofMedicine, has been suggested that British above probes. In the Scottish family, Cardiff. psychiatrists are wrongly applying the the maximum lod score was 6-27 at diagnosis to unfamiliar, culturally 0=0 1 showing definite linkage. The Family, twin, and adoption studies determined patterns of behaviour J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

564 Clinical Genetics Society

induced by stress. Previous research None of the benign or borderline Gene probe analysis in MEN 2A: has shown that genetic factors are tumours was seen to lose alleles at these early exclusion, diagnosis, and important in the aetiology of schizo- loci, apart from one benign tumour treatment phrenia. We have therefore used a which appeared to have lost a copy of P J MORRISON*, A E HUGHES*, standardised family history method pBHP53. Work has also been started to N C NEVIN*, D R HADDENt, (FH-RDC) to compare the first degree assess the allele loss status for chromo- A L KENNEDYt, C F J RUSSELLt relatives of 36 Afro-Caribbean and 39 some 18 using DCC probes in the same *Department ofMedical Genetics, native Caucasian patients treated for tumours. Loss of chromosome 18q The Queen's University ofBelfast; schizophrenia in Central Manchester material has been found to be common tSir George E Clark Metabolic Unit, between 1982 and 1988. Lifetime in other cancers, including breast and Royal Victoria Hospital, Belfast. morbid risk was 9 0% for parents of colon cancer. Preliminary results Afro-Caribbean subjects and 8-4% for suggest that allele loss is low in our Multiple endocrine neoplasia type 2A parents of Caucasian subjects. These sporadically occurring tumours. Signi- (MEN 2A) is an autosomal dominant observations suggest that schizophrenia ficantly, however, we have detected genetic disorder consisting ofmedullary among Afro-Caribbeans is no less DCC allele loss in a familial ovarian thyroid carcinoma, adrenal tumours, familial than for the general population. and a familial breast tumour, which are and parathyroid adenomas. Analysis The risk for sibs of Afro-Caribbean both from a large breast/ovarian cancer using the markers TB10. 163, RBP3, probands was 16-2%, compared with family. It will be important to ascertain and TB14.34, flanking the MEN 2A 1-8% for sibs of native subjects if a germline mutation in the DCC gene gene locus on chromosome 10 has been (p<005). Sibs of UK born Caribbean is segregating with predisposition to undertaken in a four generation kindred probands had even higher morbid risks tumour formation in this family. with ages ranging from 1 to 90 years, in (27-3%). These data are consistent which several members are affected. with a similar degree of genetic pre- Penetrance and age of onset vary con- disposition in both ethnic groups, siderably in this condition and early interacting with an environmental undetected tumour metastasis may precipitant which is more prevalent Familial adenomatous polyposis result in early patient death. Results in among young people ofAfro-Caribbean coli (FAPC) and mental handicap in all four generations of the family allow origin. two generations owing to recurrent carrier risks originally based only on deletions resulting from a basal serum calcitonin studies to be chromosome 5 rearrangement significantly altered by the use of the (ins(5Xq31.3q22q23.2) gene probe data; this allowed early Detection of allele loss in ovarian I CROSS, J DELHANTY, P CHAPMAN, diagnosis of two affected patients cancer D GRIFFIN, J WOLSTENHOLME, under 20 years old in generation IV and M BRADBURN, A GUNN, J BURN exclusion of 11 patients from all four B MILNER', N HAITES ', generations from having the disease. K KELLY*, S MCKENZIE*, M HALLt, Northern Region Genetics Service, This facilitates early surgical treatment http://jmg.bmj.com/ H KITCHENERt, D PARKINt, University of Newcastle upon Tyne; A JOHNSTON * Galton Laboratory, UCL, London. and may prevent early tumour meta- Departments ofMolecular and Cell,- stasis, and allows excluded patients to Biology (Medical Genetics)*, and The proband, a mildly retarded adult be discharged from review clinics. Obstetrics and Gynaecologyt, male, presented with a duodenal Foresterhill, Aberdeen. adenoma and was then found to have polyps on colonoscopy. At colectomy Dystrophin abnormality in autosomal DNA has been analysed from 44 ovarian there were microscopic polyps recessive (?) Duchenne-like

tumours, of which 22 were malignant throughout the bowel though none was muscular dystrophy on September 24, 2021 by guest. Protected copyright. and 12 were of borderline malignancy. visible in the descending colon. His J-U WALTHER*, TH DEUFELt, Using a panel of chromosome 17 mother had died and had been handi- TH MEITINGER*, D PONGRATZt probes, tumour and normal DNA have capped. Her parents were normal but a Kinderpoliklinik mitAbtfp2d. Genetik*, been compared in a 'loss of hetero- sister was retarded and on examination Kinderklinikt, and Friederich-Baur- zygosity' study. All malignant tumours also had FAPC. Both affected subjects Stiftung* der Universitat Munchen. proved to be informative for at least had multiple areas of congenital hyper- two of these chromosomal markers, trophyofthe retinal pigment epithelium The second of two daughters of con- indicating allele loss as shown below. (CHRPEs) and a deletion of 5q22- sanguineous Sinti parents with no q23.2. A normal aunt of the proband family history presented with proximal was found to have this segment muscle weakness at 5 years of age. The DNA probe No of tumours showing loss inserted at 5q31.3. This arrangement symptoms have progressed ever since: pYNZ22 (17pl3.3) 12/22 requires a double insertion loop. Cross- at 9 years her clinical picture is typical (55%) over within the loop had produced the of (Duchenne) muscular dystrophy pYNH37.3 (17p13.3) 1/1 deletion in two family members. In situ with generalised muscular wasting with (100%) shoulder pMCT35.1 (17pl3.1) 4/8 hybridisation showed both copies of pelvic and girdle pre- (50%) ECB27 to be present which placed the dominance, pseudohypertrophy of the pBHP53 (17pl3.1) 2/9 proximal break between this marker calves, and Gower's sign. Humoral, (22%) and the APC gene. Comparison with EMG, and biopsy findings are indica- pTHH59 (17q23-qter) 10/17 the two other deletion cases indicates tive of (D)MD. A normal karyotype (59%) the APC gene is within band q22. excludes chromosomal anomalies as a J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

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likely cause of extremely skewed against age. The larger group (57 anatomy. All scans are performed by Lyonisation, gene disruption, or hemi- patients) had relatively mild disease radiographers who have between one zygosity. The pedigree favours homo- (average age of becoming wheelchair and 10 (average two) years' experience zygosity for an autosomal recessive bound 58 years). All the deletions of obstetric ultrasound. Examination mutation as claimed, among others, by detected in this group were in the area includes measurement of the biparietal Somer et al (Clin Genet 1985;28:151-6). of exons 45 to 54 of the dystrophin diameter, head circumference, and Molecular studies have failed to gene. The dystrophin in these patients femur length and careful inspection of identify an anomaly of the dystrophin was of reduced size, inversely pro- the fetal head, intracranial anatomy, gene. Immunofluorescence showed portional to the amount of coding spine, heart, diaphragm, stomach, generalised, somewhat patchy presence sequence lost, and of variably reduced anterior abdominal wall, kidneys, of dystrophin in decreased amount. abundance (30 to 97% of control) with bladder, and limbs. If at the first Western blot analysis showed a nor- the presence of a characteristic 'de- examination the fetus is found to be mally migrating dystrophin band of gradation band'. Three patients in less than 18 weeks or there is difficulty markedly reducedquantity as compared this group had no cDNA deletion and a in completing the examination satis- with controls. Thus, both dystrophin full sized dystrophin molecule pro- factorily, the woman is asked to attend findings resemble those in hemizygous duced at reduced abundance. None of for a second scan. When an abnormality patients with Becker muscular dys- the nine patients in the severe group is detected the findings are discussed trophy. This contrasts with the clinical (average age of becoming wheelchair with the obstetrician and parents and, severity of the myopathy. Non-invasive bound 26 years) had a deletion or in selected cases, the woman is referred investigations of the parents so far have dystrophin pattern similar to those to a tertiary centre for confirmation of not detected any related abnormality. seen in the typical group. This group the anomaly and further investigations Differential diagnosis must consider was more heterogeneous clinically and or management as necessary. We have autosomal recessive (Duchenne-like) at both the gene and protein level, with reviewed this policy over a two year muscular dystrophy (ethnic origin of the genetic defects seen including no period starting from January 1988. the family), a severe case of limb girdle detectable cDNA deletion, a very large Outcome was confirmed by inspection muscular dystrophy, and overlooked in frame deletion, and a duplication. of the neonatal notes or pathology tissue hemizygosity from XX/XO We conclude that the majority of reports. A computerised record is kept mosaicism. The dystrophin findings patients with BMD follow a relatively of all neonatal abnormalities detected will be discussed in relation to these mild clinical course and that this before infants leave hospital and this alternatives taking into account the phenotype is often associated with was inspected for any abnormalities recent identification and mapping of characteristic deletion and dystrophin which were not detected prenatally. A autosomal DNA sequences with pro- patterns. total of 8733 infants was born during nounced dystrophin homology (Buckle the period of the study. Approximately et al, Hum Genet 1990;85:324-6). The value of routine ultrasound for 95% were examined with ultrasound in the detection of fetal abnormalities the second trimester. Fifty-two preg- http://jmg.bmj.com/ Becker muscular dystrophy: LYN S CHITI1Y, MICHAEL 0 LOBB nancies were terminated after the correlation of phenotype, gene, and Department ofClinical Genetics, identification of a fetal malformation. protein Institute of Child Health, 30 Guilford Of the fetuses which were examined in K M D BUSHBY, D GARDNER-MEDWIN, Street, London WCI IEH; Luton and the second trimester, 124 had a signi- L V B NICHOLSON, D HAGGERTY, Dunstable Hospital, Luton, ficant structural abnormality confirmed S S BHATTACHARYA Bedfordshire. at the end of pregnancy. In 92 (74-2%, Departments ofHuman Genetics and 95% CI 67-7 to 80 4) cases the abnor- Neurobiology, University ofNewcastle Prenatal ultrasound can detect many mality was diagnosed with ultrasound upon Tyne. fetal malformations about 90%/o of before 24 weeks. Of the 124 abnor- on September 24, 2021 by guest. Protected copyright. which occur in fetuses born to parents malities, 65 were lethal or severely Now that it is possible to identify with no recognisable risk factors. crippling. Fifty-six of these were deletions in the dystrophin gene and to While there is much evidence to detected by the routine screening quantify dystrophin abnormalities in suggest that routine ultrasound screen- programme (sensitivity 87-1%, 95% CI muscle samples by immunoblotting, ing in the second trimester improves 79-3 to 94-9). Of the 8609 normal the phenotype of Becker muscular the diagnosis of multiple pregnancies fetuses there were four false positive dystrophy (BMD) can be correlated and the estimation of the expected date diagnoses, all resulting in the birth of with the molecular defect at both the of delivery, there are few data available an apparently normal infant. This gives gene and protein level. Wehaveassessed on its use for routine screening for a specificity of 99-95% (95% CI 99-93 66 patients with BMD according to a congenital malformations. We will to 99-97). We conclude that routine detailed protocol, including a full discuss the results of our routine fetal fetal ultrasound examination in a low history, functional and muscle exami- ultrasound programme at Luton and risk population detects many fetal nation, DNA analysis, and dystrophin Dunstable Hospital which is a district malformations but it can present several analysis. This has allowed a redefmnition general hospital where about 4400 dilemmas in counselling. of the course of the disease in a large women are delivered annually. All cohort of patients, including 37 women who book early enough for sporadic cases in whom the diagnosis prenatal care are offered an ultrasound A prospective trial of prenatal could not previously have been con- scan at between 18 to 20 weeks' screening for chromosome firmed. Two groups emerged from gestation to confirm fetal viability and abnormalities using maternal serum graphs of functional and muscle score gestational age and examine the fetal hCG and AFP levels J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

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J A CROSSLEY, G MCCAW, ductus arteriosus, five (15%) isolated the offer of carrier testing; 16 were D A AITKEN, A CAMERON, ventricular septal defects, and three minors, in whom carrier testing has J M PONT, M J WHITTLE, (9%) complex CHD. Clinical exami- been deferred. Determinants for J M CONNOR nation alone was an insensitive test for screening included anxieties arising in Duncan Guthrie Institute of Medical CHD (0-51) but this was improved a current pregnancy, personal or off- Genetics; Glasgow Royal Maternity when CXR and ECG were added spring health concerns, and family Hospital; Rutherglen Maternity (sensitivity 0-71, specificity 0 91). ECG pressure. Hospital; Queen Mother's Hospital, was highly specific for CHD but lack of Glasgow. experience in interpretation may Mutation analysis in the CFTR reduce its effectiveness. In centres gene in Northern Ireland and Retrospective studies have shown that where surgery is offered for CHD in comparisons by combining risks from hCG and genotype:phenotype Down's syndrome early detection and A J M HILL*, C A GRAHAM*, AFP levels with maternal age risks, a follow up of heart defects is important, P K C GOON, A C MAGEE*, possible 57% detection rate for Down's in order to minimise the risk of later A REDMONDt, N C NEVIN* syndrome may be achieved for a falie presentation with, for example, *Regional Genetics Centre, Belfast City positive rate of 5%, while low hCG pulmonary vascular disease. We Hospital, Belfast BT9 7AB; levels are a useful predictor of trisomy recommend that all Down's syndrome 18. Between July 1989 and June 1990, fRoyal Belfast Hospitalfor babies have an echocardiograph in Sick Children. as part of a prospective blind trial, we early postnatal life. have routinely measured hCG in all Cystic fibrosis patients in Northern samples sent for AFP screening from Ireland are now routinely screened for three Glasgow maternity hospitals Carrier testing for CFTR gene a series of mutations in exons 4, 10, (total 7830 pregnancies). Nine-out of mutations in relatives identified and 11 of the CFTR gene, with an 15 (60%) singleton pregnancies with through a cystic fibrosis prenatal overall mutation detection rate of 74%. Down's syndrome identified within the testing service: response rates Exon 10 mutations, AF508 and A1507, screened group had hCG levels greater and determinants of uptake account for only 57% of CF mutations than 2-0 MOM, and eight of the R C TREMBATH*, J GREENt, in this region. The exon 11 mutations, trisomy 21 pregnancies (53%) could be C MCMAHON*, S MALCOLM*, G551D, G542X, and R560T, together detected using risks derived from hCG M E PEMBREY* account for almost 13% of mutations. and AFP levels and maternal age, with KDepartment of Paediatric Genetics, G542X is found at the same frequency a false positive rate of5-6%. In addition, Institute of Child Health; (4%) as in other populations, while two pregnancies with trisomy 18 had tSt Maty's Hospital, London. R560T (4 1%) is unusually high. hCG levels less than 0-3 MOM. These G551D occurs at similar frequencies in results confirm the effectiveness of The identification of the common CF patients throughout northern combined hCG/AFP/age screening in mutations in the CFTR gene have Europe (4-7% in Northern Ireland)

prospective clinical practice. paved the way for the introduction of and is associated with an X1K2 haplo- http://jmg.bmj.com/ population based cystic fibrosis (CF) type in 100% of cases here, suggesting Screening for congenital heart carrier testing. The acceptability and that it spread through a founder effect. disease (CHD) in Down's syndrome: response of the general population to The exon 4 mutations 556delA and 621 a two year prospective study carrier testing for this common genetic + 1G>T account for 3-3% of CF T R J TUBMAN, M D SHIELDS, disorder is unknown. We have surveyed mutations, the latter being unusually N C NEVIN, B G CRAIG, a group of subjects, identified through high in this region. We have now H C MULHOLLAND relatives with detectable mutations of identified patients with 12 fully defined Royal Belfast Hospitalfor Sick Children the CFTR gene, and who are at greater mutation genotypes and have started to and Northern Ireland Genetics Service, than the population carrier risk for CF. look for possible relationships between on September 24, 2021 by guest. Protected copyright. Belfast City Hospital. Between 1986 and early 1990, the genotypes and disease severity. Clinical Regional Genetic service counselled and details have been collected on 63 We prospectively screened all Down's provided prenatal testing for CF in patients, 32 are homozygous for AF508 syndrome babies born in Northern 74 couples. All contactable subjects in and 31 have other fully defined Ireland from November 1987 to 1989 this cohort, 1 15 (83%), with a detectable mutations. These have been divided for CHD: 81 babies (1-45/1000 live mutation were notified by letter. In into three groups: (A) those involving births) were screened by clinical ex- addition they were invited to provide exon 10 mutations only, (B) those with amination, chest radiography (CXR), details of those close relatives whom an exon 10 mutation on one chromo- and ECG as soon after birth as poss- they believed may wish to have CF some and an exon 11 mutation on the ible, followed by 2D Doppler echo- carrier testing. Replies were received other, and (C) those with an exon 4 cardiography performed by the from 61 (53%) of index cases, with 51 mutation on one chromosome and an regional paediatric cardiology service. subjects nominating a total of 93 exon 10 or 11 mutation on the other. Sixty-one (75%) had an echocardio- relatives. Thirty-nine have accepted The results are summarised below. graph in the first two weeks of life and 91% before 3 months of age. Thirty- Chest symptoms Severity Exons with Age Av Pseudo- four babies (42%) had echocardio- mutations range Mild (1) Moderate (2) Severe (3) score monas PI MI graphic evidence of CHD; of these 13 (38%) had atrioventricular septal A. 10/10 1-26 16 17 4 1-7 13 37 2 5 5 9 5 seven secundum atrial B. 10/11 3-26 2-2 19 1 defects, (20%) C.4/lOorll 0-8 6 - 1 1-3 1 7 - defects, six (18%) solitary patent J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

Clinical Genetics Society 567

Genetic enquiry into medical GILLIAN B INGALL large (20 to 40 kb) DNA inserts. services. A national confidential Division of Genetics and Metabolism, Specific hybridisation is detected with enquiry into the quality of genetic Children's Hospital of Michigan, avidin or antibodies conjugated with diagnosis, risk estimation, and Wayne State University, Detroit, fluorescein isothiocyanate or Texas counselling provided by family Michigan 48201, USA. Red, and visualised using a MRC practitioners and hospital specialists Lasersharp confocal microscope. We RODNEY HARRIS, ANWAR KHAN, Recent reports on genetic services in present examples showing the pre- ANTHONY HOPKINS the United Kingdom indicate that cision of the technique in mapping Department of Medical Genetics, there is an increasing demand for non- cosmid DNA to banded chromosomes. Manchester, and Research Unit, medical genetic counsellors. This is in In addition, FISH enables rapid Royal College of Physicians, London. part the result of the expansion of pre- confirmation of the origin of cosmid natal diagnostic capabilities, and of clones selected by the screening of Because of rapid scientific advances, the ever increasing possibilities of libraries. For example, in one instance, public expectations, and resulting genetic diagnoses through DNA tech- two of four selected clones proved to be workloads, GPs and hospital specialists nology. The role has evolved in the outside the region under investigation. are taking on genetic counselling and United States over the past 25 years. Thus, we consider FISH to be an management for which they have Training is standardised to include a essential part of the analysis of cosmid usually not been trained. Under- Master's degree in genetic counselling clones. graduate and postgraduate medical leading to accreditation by examination teaching in genetics is at best patchy, through the American Board ofMedical and often deficient, and will take some Genetics. The majority ofgraduates are Meiotic segregation in translocation time to improve. Following a feasibility neither nurses nor social workers. heterozygotes analysed by study carried out with the help of There is no structure for career fluorescence in situ hybridisation clinical geneticists, the Royal College advancement, so future recruitment A S H GOLDMAN, M A HULTEN of Physicians of London, with the may be threatened. However, such Regional Genetic Servces, cooperation of other medical Royal counsellors have become an integral DNA Laboratory, East Birmingham Colleges, the BPA, the ACC, CGS, part of genetic centres supplementing Hospital, Yardley Green Road, CMGS, GIG, the Department of the role of the clinical geneticist, parti- Birmingham B9 SPX. Health, and others is about to launch a cularly in the prenatal arena. This may Confidential Enquiry into the way in part be explained by the different Carriers of chromosome rearrange- genetic problems are managed by non- health care systems in the USA, ments, such as translocations, generally geneticists. The Enquiry will be anony- ranging from the privately insured to suffer an impairment in reproduction. mous and non-censorious relying on the welfare population. There is some This reproductive disturbance includes paediatricians, obstetricians, surgeons, concern as to the future of Master's sterility and subfertility, that is, and others to review their own patients' trained genetic counsellors in the habitual abortion, and an increased records by comparing them with USA. The need is proven but it is risk for intrauterine and neonatal http://jmg.bmj.com/ clinical guidelines in the form of unlikely to be met unless a better deaths as well as multiply malformed questionnaires for each of the 'marker career ladder is developed. The UK and/or mentally retarded children. disorders'. Initially Down's, NTD, has an opportunity to avoid this Theempirical riskmay varyenormously cystic fibrosis, haemophilia, thalas- dilemma by training nurses, public between carriers/families, in fact from saemia, multiple endocrine neoplasia health in particular, to undertake a 1 to I100/o. However, it is often im- type 2, and FAP have been selected by similar role of genetic counsellor. They possible tocalculateanadequate specific the Steering Group. Each disorder has could have the advantage of having risk for the individual family. Such

a convenor and working group who are other recognised skills and an estab- accurate information is available from on September 24, 2021 by guest. Protected copyright. currently planning ascertainment and lished career structure. the direct study of gametes, or gameto- designing questionnaires. The aims are genesis, in a constitutional carrier of a to ensure that those at risk of genetic structural rearrangement. We have disease are informed of the options Mapping cosmid clones using used the new in situ hybridisation available but eugenic considerations fluorescence non-isotopic in situ technique of chromosome painting to are explicitly excluded and the avoid- hybridisation obtain the required information from ance of genetic disease by abortion is M A LEVERSHA, N P CARTER, human testicular biopsy. Byhybridising neither advocated nor rejected. It is C A SARGENT, M A FERGUSON-SMITH for a rearranged chromosome it is regarded as essential, however, that Department of PatholoV, University of possible to count the different segre- appropriate screening for hereditary Cambridge, Tennis Court Road, gational possibilities in meiotic second cancer should be offered in good timne Cambridge CB2 IQP. metaphase nuclei, so obtaining a pre- to relatives who may benefit from diction of what proportion of gametes effective treatment. Regular reporting We are using fluorescence in situ would be normal, balanced, or un- will include any deficiencies in Health hybridisation (FISH) to localise and balanced. Service provision that are revealed by order cosmid clones on human the Enquiry. chromosomes. Cosmid DNA is labelled with biotin or digoxigenin and then A male with trisomy 9 mosaicism The role of a non-medical genetic preannealed with unlabelled genomic and uniparental chromosome 9 counsellor: can the UK benefit DNA to suppress hybridisation with disomy in the euploid celi line from experience in the USA? repetitive elements present in these LIONEL WILLATr, CLARE DAVISON, J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

568 Clinical Genetics Society

DAVID GOUDIE, JULIET ALEXANDER, sporadic cases. A deletion of chromo- paternal contribution. Patient 2 is only HELEN DYSON, PAUL JENKS some 15ql 1-13, visible on high 3 years of age, and after diagnosis the East Anglian Regional Genetics Service, resolution banding, was reported in family was referred for genetic counsel- Addenbrooke's Hospital, Hills Road, Angelman syndrome by Kaplan and by ling. Cytogenetic studies showed that Cambridge CB2 2QQ. Magenis in 1987 and by Pembrey in she also did not carry a 15ql1-13 1988. This has been confirmed as a deletion, but again had inherited both We describe a 17 year old male with frequent finding in AS by other maternal chromosomes 15. In this case congenital malformations who was groups. We have studied 77 patients satellite polymorphisms from her found to have trisomy 9 mosaicism. with AS from 71 families and have father showed non-inheritance of his Trisomy 9 was found in seven of 100 carried out detailed cytogenetic and chromosomes 15. In both patients cells in blood lymphocyte cultures, but molecular genetic analyses. Forty-one other polymorphisms were consistent no cells with trisomy 9 were seen in patients (55%) had a de novo deletion with paternity as stated. The apparent 200 cells examined from skin and of l5qI 1-13 and this was confirmed on maternal heterodisomy is supported in muscle biopsy cultures. A pericentric DNA analysis in 13 cases. In 32 cases both cases by molecular studies using inversion of the heterochromatic area the cytogenetic examination was probes specific for chromosome 15. of chromosome 9 (p1 1q12) was identi- normal. This group included the 11 fied in the patient and his mother. This familial cases and two with uniparental variant was present in duplicate in both paternal disomy for the whole of the trisomic and the euploid cells chromosome 15. Four patients had indicating that the trisomy 9 cell line a rearrangement or irregularity of Prader-Willi syndrome in had arisen following a maternal meiosis chromosome 15. AS arises as a result of Northern Ireland II error with subsequent postzygotic several different genetic mechanisms. F J PRIEST, N C NEVIN, I RENNIE loss of the paternal chromosome 9 in The de novo deletion group and those Department ofMedical Genetics, the euploid cell line. Molecular studies with uniparental disomy are the groups Belfast City Hospital. with the probes LAMP92, ASSG3, and at low risk of recurrence. Thirty-seven HF12-8 (D9SI) confirmed that there per cent of our cases fell into the no Northern Ireland has a population of had been loss of the paternal chromo- deletion/no disomy groupfor which the 1 5 million people with 28 000 births some 9 in the euploid cell line and that recurrence risk is high and the mech- per year. A review of all patients with there had been a crossover between the anism as yet unexplained. Elucidation PWS has been continuing since 1989 maternal chromosome 9 during meiosis of the mode of inheritance in each case with a view to ascertaining clinical I. To our knowledge this is the first of AS is important for accurate genetic problems, estimating the prevalence in case of trisomy 9 mosaicism in which counselling. the population, and investigating the the mode of, and parental, origin have cytogenetic and molecular aspects been confirmed. A maternally derived within the families. The main source of pericentric inversion of chromosome 9 ascertainment was the records of the has been observed in three other Posters Regional Genetic Service. In addition, http://jmg.bmj.com/ reported cases of trisomy 9 mosaicism paediatricians were asked to identify and in all cases the variant chromosome Maternal heterodisomy in patients in their care. A total of 17 was present in two copies in the Prader-Willi syndrome patients was examined, 13 had the trisomic cell line. The lack ofa paternal P FARNDON, M GRIFFITHS, diagnosis of PWS confirmed, and four chromosome 9 in the euploid cell line D CLARKE, C HARDY, M KILPATRICK, had the diagnosis amended. Twelve of and the low level of mosaicism for the T WEBB the 13 were aged between 7 months Departments of Clinical Genetics and and 14 years; one female patient was trisomic cell line will be discussed in Cytogenetics, Birmingham Maternity relation to the clinical findings in this aged 27 years. The clinical findings are on September 24, 2021 by guest. Protected copyright. patient. Hospital, Edgbaston, Birmingham as follows: hypotonia (at birth) (13/13); B15 2TG. blue irides (12/13); fair hair (6/13); scoliosis (7/13); strabismus (6/13); Two subjects with typical Prader-Willi weight <90th centile (5/13); skin syndrome are presented, along with picking and irritation (1/13); acanthosis Genetic mechanisms and recurrence their families. They are not related and nigricans (1/13). Hyperphagia was a risks in Angelman syndrome were ascertained by different methods. universal feature in the older children. J CLAYTON-SMITH, T WEBB, Patient 1 wasinvestigatedinconjunction As 11 possible PWS patients have not, M E PEMBREY, S MALCOLM with a research project on Prader-Willi to date, cooperated, an accurate pre- Institute of Child Health, London, and syndrome. She is 32 years of age, the valence rate cannot be calculated. Birmingham Maternity Hospital. youngest of five children, and cyto- Assuming that in 70% of these patients genetic studies indicated that she did the diagnosis is correct, the total Angelman syndrome (AS) is a cause of not have a 15qll-13 deletion. She number of PWS patients aged between severe mental retardation associated had, however, inherited one mater- 0 and 14 years in Northern Ireland withcharacteristicdysmorphic features. nal chromosome with extra material would be 19. The population in this It is usually sporadic in occurrence but in 15p. This distinctive cytogenetic age group in 1988 was 395 800. The several families have been reported polymorphism for one chromosome prevalence rate for PWS is approxi- where there is more than one affected along with NOR staining for the other mately 1 in 20 000. Cytogenetic analysis child. These subjects are indistinguish- indicated that she had inherited both of showed eight out of 13 patients to have able clinically and on EEG from the her mother's chromosomes 15 with no deletion 15ql1.2. J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

Clinical Genetics Society 569

Severe prenatal Caffey's disease: found no association between radiation D A AITKEN, R SOUTAR, fetal phenotype exposure and Down's syndrome. J L TOLMIE, B GIBSON, R DAY, P D TURNPENNY Sheehan and Hillary (BMJ 1983;287: J B P STEPHENSON Medical Genetics, Foresterhill, Aberdeen. 1428-9), however, reported an apparent Duncan Guthrie Institute of cluster of Down's syndrome in children Medical Genetics; Department of Caffey's disease, infantile cortical born to a group ofwomen who attended Haematology, Fraser ofAllander hyperostosis, has been extensively the same school on the east coast of Assessment Unit, Yorkhill, Glasgow reported and is an autosomal dominant Ireland, a region which was claimed to G3 8SJ. trait with reduced penetrance. It is a have been exposed to radiation follow- self-limiting condition of unknown ingthe fireat Sellafield (then Windscale) Family 1. The first child of non- aetiology characterised by painful in 1957. We have identified 515 cases consanguineous parents presented at swelling ofthe soft tissues, hyperostotic of Down's syndrome occurring in the 13 months with unexplained mild bone changes, and fever. Clinical onset Northern Regional Health Authority spastic quadriplegia. Haematological is in early infancy with resolution during the period of 1979 to 1989. The investigation at the age of 3 years usually by 3 years. The mandible is address at birth was identified and this showed lymphopenia with undetectable most frequently affected (800/%), some- was used as a reference point for cluster T lymphocytes. A complete deficiency times causing 'cherubic' facies. Prenatal analysis. The technique applied was of purine nucleoside phosphorylase onset of the disease is also described one developed by Besag and Newell for (PNP) activity and raised adenosine (approximately 25 cases) and six have the detection of small clusters of rare deaminase (ADA) activity was found in shown a severe phenotype characterised diseases. No significant clusters of red cells from the proband. The parents bypolyhydramnios, generalised skeletal Down's syndrome have been identified had half normal levels of PNP activity. hyperostosis, and short and oedematous in West Cumbria. Prenatal diagnosis by CVS was under- extremities. Survival in two occurred taken at 10 weeks' gestation in a when the pregnancy reached term, but subsequent pregnancy. Undetectable four were intrauterine or early neonatal Neonatally lethal hydronephrosis PNP activity with normal ADA deaths, extremely premature, and and renal agenesis in the third activity was found in direct CVS pre- sporadic. Anadditional case ispresented generation of a dominant pedigree parations indicating an affected fetus. in a 27 week fetus born to consan- with hydronephrosis: variable Family 2. PNP deficiency was shown guineous parents. The features were: expression or anticipation? retrospectively in this family in which a coarse facies, shallow nasal bridge, D P MCHALE, S ANDRONIKOU, sister and brother, born in 1%3 and corneal clouding, generalised limb E N HEY, J BURN 1966, had disequilibrium-diplegia and shortening, oedematous and rigid soft Departments of Human Genetics cellular immunodeficiency. Both tissues, and hepatomegaly. Radio- and Child Health, University of children died and were thought to have logically there was a narrow, bell Newcastle upon Tyne. a 'new' clinical entity: familial ataxic shaped thorax with small lung fields diplegia with deficient cellular im- suggesting pulmonary hypoplasia, and Primary hydronephrosis (McKusick munity (MIM 209000). Subsequently, http://jmg.bmj.com/ generalised skeletal hyperostosis 14340) is presumed to be a variable fibroblast cultures from the second sparing the cranial vault, vertebrae, autosomal dominant disorder though child, which had ben stored in liquid and clavicles. there are only two three generation nitrogen for 17 years, were successfully pedigrees published (Cannon A, Intern reconstituted and shown to have un- Med 1954;41:1054-60, Jewell and detectable PNP activity but normal Geographical distribution of Down's Buchert, J Urol 1%2;88:129-36). In ADA activity. Both parents had half syndrome in the Northern Region 1955 Raffle (BMJ 1955;ii:580-2) normal erythrocyte PNP activity. reported four cases in two generations 0 M WILSON, J NEWELL, C CLARK, on September 24, 2021 by guest. Protected copyright. J J of a North East family. The pedigree WOLSTENHOLME, TAWN, now contains six living affected A CRAFT, J BURN Second trimester unconjugated Departments of Human Genetics members, one of whom presented with oestriol levels in maternal serum and Child Health, University of a history of two unsuccessful preg- from chromosomally abnormal Newcastle upon Tyne. nancies. The first was a neonatal death with hydronephrosis and the second pregnancies using an optimised assay had bilateral renal agenesis. These may J A CROSSLEY, D A AITKEN, The recent report of an association J M CONNOR between parental exposure to radiation be coincidental or may represent a Duncan Guthrie Institute of at Sellafield and a cluster of cases of more extreme form of a variable Medical Genetics, Yorkhill, Glasgow childhood leukaemia has reopened the expression. A third possibility is that G3 8SJ. question of whether genetic defects this is an example of true anticipation. may result from paternal Whatever the explanation, account irradiation must Unconjugated oestriol (UE3) levels, and has also renewed interest in press be taken of the need to offer fetal measured using modifications of reports of clustering of anomaly scanning when counselling Down's syn- such families. commercially available immunoassay drome in West Cumbria. Studies of kits designed for use in the third chronic exposure to low level radiation trimester, have been reported to be as a possible cause for non-disjunction Two families with purine nucleoside significantly lower in second trimester leading to Down's syndrome have phosphorylase deficiency: maternal serum samples from Down's yielded conflicting reports. Sever et al clinical features, enzymology, and syndrome pregnancies. We report here (Am J Epidemiol 1988;127:226-42) early prenatal diagnosis a retrospective study of UE3 levels in J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

570 Clinical Genetics Society the second trimester in maternal serum locations, four balanced translocations, Fetal sexing of amniotic fluids using from 78 chromosomally abnormal nine sex chromosome abnormalities) the polymerase chain reaction pregnancies and 390 matched controls, and 390 matched controls, and com- G W SMITH, J NEVIN, C A GRAHAM using a new immunoassay kit (Amer- pared the results with those found for Regional Genetics Centre, sham AMERLEX-M) optimised for the whole molecule hCG. The median Belfast City Hospital, Belfast B79 7AB. use at the lower second trimester free Pi hCG level in the Down's preg- concentrations. Reduced levels of UE3 nancies was further raised at 2-3 MOM The polymerase chain reaction (PCR) were found in a group of 49 Down's of the control group. However, the was used to amplify a Y chromosome syndrome pregnancies with a median wider distribution of free K subunit specific repeat sequence and an Alu UE3 value of 0-79 multiples of the levels in both Down's syndrome and repeat sequence, as a control, in 125 median (MOM) of the controls. All unaffected pregnancies resulted in loss samples of amniotic fluid taken for four trisomy 18 pregnancies had UE3 of sensitivity when free P subunit levels routine chromosome analysis. DNA levels less than 0 7 MOM. There was a are used as a predictor of trisomy 21 was extracted from cells spun from significant level of correlation between pregnancies. 500 RI of fluid using a method using AFP and UE3 levels in the controls guanidine hydrochloride and protease (r=0-25, p<0-01), the Down's syn- K; this was necessary to achieve reliable drome pregnancies (r=0 44, p<0-01), amplification. The results of the PCR and the other chromosome abnormali- test were later compared with the ties (r=0-61, p<0-01). Thus, UE3, Variation in the levels of pregnancy karyotype analysis as shown by standard when used as an additional marker to specific B-1 glycoprotein in cytogenetic methods. The success rate AFP and hCG in screening for chromo- maternal serum from chromosomaily was compared to that obtained using some abnormalities, adds little to the abnormal pregnancies fluorescence microscopy following sensitivity of such screening. G W GRAHAM, J A CROSSLEY, treatment of the amniocytes with D A AITKEN, J M CONNOR quinacrine dihydrochloride. Of the Duncan Guthrie Institute of samples tested using PCR, 121/125 Medical Genetics, Yorkhill, Glasgow (96 8%) agreed with the karyotype. Free 0 hCG and prenatal screening G3 8SJ7. Two samples gave a conflicting result for chromosome abnormalities and two failed to amplify. Of the J A CROSSLEY, D A AITKEN, Pregnancy specific a-1 glycoprotein samples sexed using fluorescence J M CONNOR (SP-1) levels were assayed by immuno- microscopy, 139/150 (92-7%) agreed Duncan Guthrie Institute of electrophoresis in maternal serum with the karyotype, six samples gave a Medical Genetics, Yorkhill, Glasgow samples at 15 to 20 weeks' gestation conflicting result, and five samples G3 8S7. from 81 pregnancies with fetal chromo- gave no result. Thus, the PCR pro- some abnormalities (48 trisomy 21, cedure can increase both the accuracy Prenatal screening for chromosome eight trisomy 18, four trisomy 13, eight and the success rate of fetal sexing abnormalities using a combination of unbalanced translocations, four from samples of amniotic fluid. The http://jmg.bmj.com/ the risks derived from maternal age, balanced translocations, and nine sex PCR test is also much more rapid and maternal serum AFP, UE3, and hCG chromosome abnormalities), and a uses much less hands on time than the has shown that 60% detection of control group of 397 chromosomally microscopy technique. Down's syndrome can be achieved for normal pregnancies, matched for a 5% follow up rate. Ofthese pregnancy gestation and maternal age. SP-1 levels markers the most powerful predictor is in the controls show a log-gaussian Early and conventional hCG which is present at increased distribution with the median SP-1 amniocentesis: a comparison of

concentration in maternal serum from concentration increasing with advanc- pregnancy outcome on September 24, 2021 by guest. Protected copyright. pregnancies with Down's syndrome. In ing maternal age. Conversion of SP-1 A C MAGEE*, F J PRIEST*, a recent study, we have found the levels in individual chromosomally N C NEVIN*, J NEVIN, J C DORNANt, median hCG value for a series of 49 abnormal pregnancies to multiples of M J ARMSTRONGt Down's syndrome pregnancies to be the median value (MOM) for the *Department ofMedical Genetics, raised at 2 18 multiples of the median control samples at the same gestation Belfast City Hospital; tRoyal (MOM) of the unaffected pregnancies. showed that the Down's pregnancies Maternity Hospital; 4jubilee Maternity These data were obtained using an were associated with a significantly Hospital, Belfast. immunoradiometric assay for whole increased SP-1 level at 1-17 MOM, molecule hCG. Assay of the free f3 with 33% of values above the 90th The joint genetic/obstetric clinic at subunit alone is possible using a mono- centile. The trisomy 18 cases and Royal Maternity and Jubilee Maternity clonal antibody which recognises an unbalanced translocations had reduced Hospitals has been offering routinely epitope on the binding site of the fi SP-1 concentrations. These trends are early amniocentesis since January 1987 subunit which is hidden in the intact similar to, but less marked than, those (Nevin et al. Prenat Diagn 1990;10: molecule. Using such an assay, we have found for hCG in the same series of 79-83). With the aspiration of amniotic analysed the concentration of the free samples. There is a strong correlation fluid at less than 14 weeks' gestation, 0i hCG molecule in maternal serum between SP-1 levels and the concen- concern has been expressed about samples from a series of 117 chromo- tration of other placental markers in possible respiratory or orthopaedic somally abnormal pregnancies (81 maternal serum, which minimises the complications in the newborn. In order Down's syndrome, 11 trisomy 18, four additional predictive value of SP-1 in to investigate these possible complica- trisomy 13, eight unbalanced trans- multiparameter prenatal screening. tions, we compared two groups of J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

Clinical Genetics Society 571

carrier screening programmes, both in Early (n=86) Conventional (n=86) the selection of a panel of mutations Mean maternal age (y) 36-4 37-6 and in risk assessment. Average gestation (wk) 11+6 16+6 Preterm labour (<35 wk) 1 7 Weight of term babies (g) 3250 3452 Clicky hips 2 2 Identification of a new mutation Talipes 0 1 (R297Q) in exon 7 of the CFTR Respiratory distress syndrome gene in a Northern Ireland family (owing to extreme prematurity) 1 I CA P K C GOON*, Congenital pneumonia 1 0 GRAHAM*, Stillbirths 0 1 A J M HILL*, G R CUTTINGt, S CURRISTANt, N C NEVIN* *Regional Genetics Centre, Belfast City Hospital, Belfast BT9 7AB; were comparable women, one group in whom the naevi (1/20) studied tJohns Hopkins Hospital, Baltimore. mothers had amniocentesis at, or to the normal subjects screened below, 13 weeks' gestation and the (8/162) and with the previously We would like to report on the identi- other group at, or above, 16 weeks' reported normal incidence. No carriers fication of a G to A mutation at position gestation. The patients were identified were found in the patients suffering 1022 in exon 7 of the CFTR gene, by selecting consecutive amniocenteses from malignant melanoma (0/166, causing an arginine to glutamine in each group, from the prenatal p=0 007). This presents the possibility change at codon 297 (R297Q). This laboratory register. Amniocenteses that a single cystic fibrosis AF508 charge change from a basic to an which resulted in an induced or spon- deletion may be protective against the uncharged amino acid is probably taneous abortion were excluded. In disease. As for the AML, in order to consistent with disease and the mutation group 1, there were 85 women and in show a two to three fold increase in risk occurs at a CG dinucleotide, a known group 2, 86. The results are shown as found in relatives of cystic fibrosis mutation hot spot. This mutation below. The findings suggest that there patients, approximately 400 to 600 creates a DdaI site; normal 270+140 is no increased incidence of respiratory AML samples would have to be anal- bp, mutant 270+106+34 bp. It was or orthopaedic complications when ysed. detected in two sibs with CF and is amniocentesis is carried out at, or associated with an X2 KI haplotype. below, 13 weeks' gestation. The other mutation in this family is Mutation analysis of two cystic also on an X2 KI haplotype and is fibrosis populations from undefined. R297Q was not detected in Northern England a further 54 CF chromosomes with undefined mutations (eight with X2 Cystic fibrosis AF508 carrier A J WALLACE*, R G ELLES*, KI haplotypes) and 50 normal chromo- frequency among patients with H HUGHESt and melanoma *Regional Molecular Genetics somes. All samples tested to date were http://jmg.bmj.com/ myeloid malignancy of Northern Irish origin. We are N WARREN*, J A HOLMESt, Department ofMedical Laboratory, additional control L L MEREDITHt, Genetics, St Mary's Hospital, currently evaluating AL-JADERf, samples to exclude the possibility that R R D C LEWIS*, Hathersage Road, Manchester WESTS, this nucleotide change represents a P J A WHITTAKERt, M13 0OH; tNorth Trent Molecular LAIDLERII, neutral Clinically the L E HUGHES*, A Genetics Service, Langhill, polymorphism. JACOBSt, girls (6 and 8 years) are similarly R A PADUAt 117 Manchester Road, Sheffield *Department ofSurgery, S10 5DN. affected with mild to moderate chest symptoms and both are receiving fLRF Preleukaemia Unit, tInstitute of on September 24, 2021 by guest. Protected copyright. Medical Genetics, 5Department of Four hundred cystic fibrosis chromo- pancreatic enzyme supplements. Epidemiology, I[Department of somes from two centres in northern Pathology, University of Wales England were screened for up to 24 Two new PCR markers in College of Medicine, Cardiff. mutations in eight exons of the CFTR the dystrophin gene gene. No significant difference in the R MOUNTFORD A comparison was made between the frequency of AF508 between the Regional Molecular Genetics Laboratory, frequency of the cystic fibrosis AF508 Manchester and Sheffield samples was St Mary's Hospital, Manchester. deletion in normal subjects and observed. The frequency of two patients suffering from acute myeloid mutations displayed markedly uneven Details are presented of the conversion leukaemia (AML), myelodysplastic distributions between the two samples, for use by the PCR technique of two syndrome (MDS), and malignant with G551D found exclusively in polymorphisms detected by dystrophin melanoma (as a solid tumour control). Manchester and R553X predominantly cDNA probes: the PstI RFLP detected This was to substantiate an earlier in Sheffield. These differences, while by the probe Cala, and the TaqI RFLP observation that the relatives ofpatients possibly the result of a local founder detected by the probe Cf23a. The suffering from cystic fibrosis were at an effect in the samples, probably illus- markers map to introns 24 and 38 increased risk ofdeveloping leukaemia, trates a steep gradient in the distribution respectively. These RFLPs supple- most notably AML (Al-Jader et al. of the two mutations across the ment the existing set of intragenic BMJ 1989;298:164). The carrier Pennines. Local and regional-vaiations PCR markers which provide a rapid frequencies in the AML (7/137), MDS in mutation frequencies such as this and efficient system of carrier detection (7/159), and a small number of benign may have important consequences for and prenatal diagnosis. J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

572 Clinical Genetics Society

Linkage analysis of Weber-Cockayne SW Thames Regional Genetics Unit, Large scale mutations at the NFI epidermolysis buliosa simplex St George's Hospital Medical School, locus in Noonan-NFI and NFI ANNE E HUGHES, KEVIN E MCKENNA, London SW17 ORE. patients W H IRWIN MCLEAN, P COLLEY, A COLLEY, N THAKKER, NORMAN C NEVIN Probe 26-6 is a close proximal marker D DONNAI, M SUPER, R HARRIS, Departments of Medical Genetics and for the APKD1 gene on chromosome T STRACHAN Dermatology, The Queen's University of 16. Published data show that this probe University Department of Belfast, Belfast City Hospital, recognises two alleles with TaqI, a 5-8 Medical Genetics, St Mary's Hospital, Belfast BT9 7AB. kb band and a 0-85 kb band, with the Manchester M13 07H. latter being the most frequent (0-73). Epidermolysis bullosa is a hetero- At a recent meeting in Leiden of the We have used a combination of short geneous group of genetic disorders EC Concerted Action on APKD, some and long range restriction mapping which can be subdivided into the groups reported a possible new poly- with intragenic and closely flanking simplex, junctional, and dystrophic morphism with 26-6, giving a band in DNA probes to investigate mutations classes. The simplex form (EBS) is the region of 1-4 kb. However, as 36-6 at the NFl locus in NFI patients, and characterised by intraepidermal blisters is quite often used in conjunction with also in NFl-Noonan (NFNS) patients. which heal without scarring. Weber- 24-1, which produces bands of 1-5 One NFl family has a deletion which Cockayne EBS (with blistering localised and/or 1-3 kb with TaqI, this informa- exceeds 200 kb and eliminates alleles at to the hands and feet) and Koebner tion was not certain. We would like to the NFC1-4 and Cll-IF10 loci. An EBS (with generalised blistering) both confirm this new polymorphism, NFNS family shows a very large show autosomal dominant inheritance. which provided data in one of our deletion which removes all markers Pooled data from Weber-Cockayne families that otherwise lacked an tested. In another NFNS family, the and Koebner EBS families have informative close proximal marker. HTF island A and the CII-IF10 suggested tentative loose linkage to the The size of the new band was 1-2 kb. locus are not deleted but the probe Duffy (Fy) blood group locus on 17L1A recognises abnormally sized chromosome lq. Recently, a Koebner BssHII, SacII, and NruI fragments, EBS family from Ireland has been which is most consistent with an reported to show linkage to the anti- insertion of about 110 kb between thrombin III gene (AT3) locus at Isolation of YAC clones containing HTF islands A and B. lq23-q25. 1. We have tested a Northern class I HLA genes which map in Irish Weber-Cockayne EBS family for the vicinity of the hereditary possible linkage to this region of haemochromatosis gene Immunological and molecular genetic chromosome 1. Polymorphisms were M M H JOUET*, L HEATHER*, characterisation of an unknown typed using DNA probes on Southern R ANANDt, R HARRIS*, structural molecule of human blots or by polymerase chain reaction T STRACHAN * connective tissues amplification and agarose or poly- *University Department of W H I MCLEAN, E MCCANN, http://jmg.bmj.com/ acrylamide gel electrophoresis. Analysis Medical Genetics, St Mary's Hospital, I D RITCHIE, B J FOGARTY, of haplotypes of three polymorphisms Manchester M13 OJH; tICI, N C NEVIN within the AT3 gene excluded close Northwich. Department ofMedical Genetics, linkage to this locus (Z<-2 at 0=0 10). The Queen's University ofBelfast, Typing of Fy blood group suggested Linkage analyses have suggested that Belfast. possible linkage (Zmax=1 01 at 0= the hereditary haemochromatosis (HH) 0-01). However, this is discounted on gene maps to chromosome 6p in the We are involved in the study of

the basis of non-linkage to the more class I HLA region, most probably in unknown connective tissue proteins by on September 24, 2021 by guest. Protected copyright. informative MUC and APOA2 loci the vicinity of the HLA-A and HLA-B means of 'forward genetics' techniques. which are thought to flank the Fy gene genes. We have designed PCR primers Human fibroblasts are known to and also to the SPTAI locus (MUC to amplify specifically HLA-A and secrete such structural proteins as Z<-2 at 0=0 07; APOA2 Z<-2 at HLA-E genes. The HLA-A specific collagens, elastin, and fibronectin 0=0 08). These results indicate that and HLA-E specific primers were used which form the basis of connective the gene causing Weber-Cockayne to screen a human YAC library con- tissues. 2D-PAGE shows that fibro- EBS in this family does not lie between taining 3-5 genome equivalents, and an blasts secrete about 50 types of glyco- the MUC and AT3 loci on chromo- average insert size of 350 kb (Anand et protein which are largely uncharac- some lq. This suggests either a location al. Nucleic Acids Res 1990;18:1951-6). terised. Here, we present data regarding distal to the AT3 gene or the possibility Streak purification of original positive the study of one of these unknown of genetic heterogeneity between the clones has led to the isolation of an proteins. A mouse monoclonal antibody Weber-Cockayne and Koebner vari- HLA-A specific YAC (insert size ca (1.4D1) was raised using live human eties of EBS. 480 kb) and an HLA-E specific YAC fibroblasts as immunogen. 2D im- (insert size ca 720 kb). Whereas the munoblots of fibroblast cellular protein HLA-A specific YAC contains multiple showed a short train of precursors of New polymorphism with probe 26-6 class I HLA genes, the HLA-E specific 141 kD and pi about 5. The extra- which proved useful as a YAC has few class I HLA genes. cellular forms were detected by proximal marker in a family Although two ferritin genes have been radioimmunotrapping assay and 2D with APKD mapped to 6p, neither YAC appears to analysis showing a double train of STEPHEN JEFFERY, MICHAEL PATTON contain a ferritin gene. 0 linked glycoproteins. Immunohisto- J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

Clinical Genetics Society 573

chemical staining showed that the cyte esterase activity by bis(4-nitro- having a balanced translocation. antigen is a structural molecule. Mono- phenyl)-phosphate results in decreased However, most reports have described clonal 1.4D1 was used toimmunoscreen monocyte cytotoxicity against the only one or two affected family an expression library in lambda gtp1 K562 erythroleukaemic cell line. members. We describe a large family using an improved detection system. A Furthermore, normal esterase positive with nine affected members result- PCR system was developed to amplify monocytes show an enhanced ability to ing from a t(4;14Xq31.3;pll.2) trans- inserts in gt1. A clone containing a lyse K562 cells when stimulated by location. All affected subjects are 1P7 kb insert is currently being lactoferrin whereas esterase negative mentally retarded with IQs ranging sequenced by a direct PCR mediated monocytes from normal subjects do not from 30 to 55. The clinical appearance technique in addition to the M13 respond to lactoferrin. These results of affected subjects is unremarkable, method. suggest that monocyte esterase has an although all are similar. The cranio- important role to play in the body's facies is characterised by brachycephaly defence mechanism against develop- with a slightly sloping forehead and Monocyte esterase deficiency ment of neoplasia. prominent nasal bridge with a straight in malignant neoplasia: a newly nasofrontal angle. The ears are large, described inherited phenomenon Interstitial deletion of 8p2l.3-23.1 low set, and posteriorly rotated with K T ENNIS*, J A MCCORMICKt, prominent antihelix, hypoplastic P J MORRISON*, J JONESt, tragus, and prominent antitragus. G M MARKEYt, T C M MORRISt N C NEVIN* *Department of Medical Genetics, *Department ofMedical Genetics, There is also micrognathia, pointed Queen's University ofBelfast; The Queen's University ofBelfast; chin, and short neck. Interestingly, fDepartment ofHaematology, two affected subjects had Hirsch- Belfast Hospital, Belfast. tRegioal Cytogenetic Laboratory, sprung's disease which has also been City Belfast City Hospital, Belfast. described in a child with duplication 4q Identification and enumeration of Partial monosomy of the distal short syndrome resulting from a t(4;9) monocvtes using cytochemical detec- arm of chromosome 8 is a rare occur- (q31;q34) translocation (Issa et al. tion of monocyte esterase activity is rence. Only 16 cases have been J Med Genet 1976;13:326-9). The large routinely used in patient haematological reported worldwide, and of these only number of affected subjects within one investigations. A 73 year old woman one interstitial deletion of 8p has been family enables a typical craniofacies presenting with a non-Hodgkin's reported. We describe a second such to be delineated for duplication lymphoma was found to be esterase case in a 6 year old female. Clinical 4q31.3-qter. negative for 95% of her monocytes. examination showed height, weight, Familial studies showed a similar level and head circumference all under the of esterase negative monocytes in her 10th centile. Dysmorphic features Duplication of lSqll.2- 15q13 in son, while two (one male, one female) included a prominent, high forehead, five cases with different phenotypes of four grandchildren registered nega- L A RAUCH, N C NEVIN

flat nasal bridge, dysplastic, low set http://jmg.bmj.com/ tive staining for between 60 to 70% of ears, orbital and nipple hypertelorism, Regional Cytogenetic Laboratory, their monocytes. A large scale survey and a small jaw. Hands and feet were Department ofMedical Genetics, monitoring the incidence of MED in puffy at birth, but this resolved within Belfast City Hospital, Belfast. patients with malignant neoplasia a few months. There was marked (n=808), patients without malignant mental and developmental delay. Red We describe five subjects with an neoplasia (n=3192), and a normal cell morphology and glutathionine apparent duplication of chromosome control population (n=474) was per- synthetase reductase (GSR) levels were 15 in the region qll.2-.ql3. The formed. Significant increases in the within normal limits. Parental chromo- patients were referred for chromosome incidence of MED were recorded somes were normal. Chromosome analysis with various clinical pheno- on September 24, 2021 by guest. Protected copyright. for patients with Hodgkin's lymphoma, analysis using high resolution GRG types. One patient had primary non-Hodgkin's lymphoma, B chronic banding confirmed breakpoints at amenorrhoea, one showed a clinical lymphocytic leukaemia, and gastro- 8p2l.3 and 8p23. 1, excluding the GSR presentation similar to the Prader- intestinal carcinoma (p=0-0018, gene from 8p2l.3 and confirming the Willi syndrome, one had insulin 010097, 01001, and 01001 respectively). locus on 8p21. The features in this case dependent diabetes with epilepsy and a An increased incidence of MED was support the suggestion of a distinct personality disorder, a baby had also found for patients attending renal distal 8p phenotype. multiple congenital abnormalities clinics (p=O-Ol12). Familial studies including wide cranial suture, en- were performed for 13 of the esterase cephalocele, and cystic brain lesion, negative patients (covering a variety of Duplication 4q syndrome resulting and one male was referred with his disorders) with 28% of first degree from a familial 4;14 translocation partner for cytogenetic investigations relatives studied registering the F J PRIEST*, M CLARKSON*, following failure of IVF. Previous deficiency. The trait appears to be N C NEVIN*, D EDGAR*, published reports indicate that duplica- inherited in an autosomal dominant G J CALVERTt tions in this region of 15q may be pattern albeit with incomplete pene- *Department ofMedical Genetics, associated with obesity, Prader-Willi trance. The increased incidence of Belfast City Hospital; orCohen syndrome, mental retardation, MED in specific disease groups implies fMuckamore Abbey Hospital, Antrim. and short stature. Two of four pheno- that the trait may predispose affected typically normal parents who were subjects to development of these Most reports of duplication 4q syn- tested were found to carry the same diseases. Inhibition of normal mono- drome result from one of the parents chromosome duplication. It is possible J Med Genet: first published as 10.1136/jmg.28.8.562 on 1 August 1991. Downloaded from

574 Clinical Genetics Soctety that the extra chromosomal material 7q21. 12- 7q31.32. Insertional trans- crossing over or by a translocation observed in our cases may be unrelated locations are relatively rare occurring at between homologous chromosomes or to the patients' clinical presentation, a frequency of 1 in 5000 births. They sister chromatids. To give rise to a since it is shown that such a rearrange- are invaluable in demonstrating the normal/duplication mosaic these events ment in the region of 15q12 is also clinical features ofpure trisomy or pure would have to occur after the first compatible with an apparently normal monosomy for chromosome segments, cleavage of a normal zygote with the phenotype. If the chromosome abnor- in this case pure trisomy for 7q21.l2 counterpart deleted clone being mality does cause the clinical symptoms 7q31.32. unviable, lost, or undetected. An alter- there is a need to explain the difference native prezygotic origin of normal/ in expression in those patients in whom duplication mosaics has been proposed, a parent has a similar duplication. Partial duplication of 16q: the half chromatid mutation model. report of a case with mosaic paternal This involves a particu'lar kind of duplication of 16q insertion between homologous or sister M W HUMPHREYS*, N C NEVIN*, chromatids occurring during meiosis. Duplication 7q resulting from E M HICKSt a maternal insertional translocation *Regional Cytogenetic Laboratory, M W HUMPHREYS, AC MAGEE, Department ofMedical Genetics, Duplication 6q syndrome N C NEVIN Belfast City Hospital, Belfast; G W SMITH, N C NEVIN Regional Cytogenetic Laboratory, tRoyal Belfast Hospital for Regional Cytogenetic Laboratory, Department of Medical Genetics, Sick Children, Belfast. Department of Medical Genetics, Belfast City Hospital, Belfast. Belfast City Hospital, Belfast BT9 7AB. We describe a female patient who We describe a male patient who pre- presented at 2 months old with dys- Duplication 6q has been described in sented at 3 days old with congenital morphic features. She was born at 42 about 20 patients and is considered to abnormalities of the hands and feet. weeks, weighing 2863 g. The antenatal have a clinically recognisable pheno- The baby was born at 39 weeks' history was unremarkable. The type. All cases have arisen from gestation weighing 2551 g. The ante- dysmorphic features included poor balanced parental translocations or natal history was unremarkable. At facial ex-pression, bilateral epicanthic inversions. We present a case of a birth, the hands and feet were twisted folds, nystagmus, alternating strabis- female infant with a de novo inverted and fingers were overlapping. When mus, posteriorly rotated ears, and a duplication of the segment 6q2l- q27 seen at 6 weeks old, the facies was prominent maxilla. The palate was which represents a pure trisomy for characterised by small eyes with high. She had marked hypotonia and this region without any associated downward slanting palpebral fissures, psychomotor delay. Echocardiogram deletion. The parents' chromosomes flat nasal bridge, small, upturned nose, showed a small atrial septal defect. were normal. The infant had multiple low set, abnormal ears, and micro- Cytogenetic investigations showed an congenital abnormalities including gnathia. The palate was high. Nipples unbalanced rearrangement of chromo- facial dysmorphism, postaxial poly- http://jmg.bmj.com/ were widely spaced. The fingers were some 16 which was determined as a dactyly of fingers and toes, ulnar long. He was not fixing his eyes tandem duplication ofregion 16q22. 1-- deviation of hands, bilateral simian and the parents considered that he had 16q24. 1. The parents have an older, creases, talipes equinovarus, short some hearing difficulty. Cytogenetic normal son. The mother and her son neck, and congenital heart anomalies examination showed extra chromo- had normal karyotypes. The father was (atrial septal defect, mitral regurgi- somal material inserted within the mosaic for the same duplicated 16, tation, and cardiomegaly). The facies short arm of chromosome 2. The with 93% of his blood cells having a was characterised by brachycephaly, male The case pre- round facies, hypertelorism, short parents had had two previous preg- normal karyotype. on September 24, 2021 by guest. Protected copyright. nancies: a spontaneous abortion at 12 sented is rare in that the proband's nose, low set ears, and microstomia. weeks and a normal daughter. The chromosome duplication is inherited The patient was the last of a sibship of father had a normal karyotype. The from a parent with the same duplication four; an older brother died at 36 hours mother was found to have an insertional in mosaic form. There are only six with the diagnosis of cot death. translocation with the chromosome previously reported cases of mosaicism Comparison of the clinical features of segment 7q21.12- 7q3l.32 inserted for a tandem duplication of any our patient with those previously into chromosome 2 at band 2pl 5. The chromosome. Chromosomal duplica- published shows that duplication 6q is patient thus has a duplication of region tions are explained either by unequal a recognisable syndrome.