J Med Genet 1990; 27: 205-210 205 J Med Genet: first published as 10.1136/jmg.27.3.205 on 1 March 1990. Downloaded from

ABSTRACTS OF THE MEETING OF THE CLINICAL GENETICS SOCIETY HELD ON 5 AND 6 OCTOBER 1989 AT MIDDLESEX HOSPITAL MEDICAL SCHOOL

Hereditary motor and sensory neuro- D4S43 and D4S95 loci, we have disease were compatible with a single pathy type I is linked to chromosome carried out predictive testing on 50 mutation model, whereas the age 17 subjects at high risk of inheriting the incidence curves for sporadic RCC and H R MIDDLETON-PRICE$, A E HARDINGt, HD gene, identified through the CHB suggested a two stage mutation C J MONTEIRO*, J BERCIANO4, Consortium arrangements. Six of these process. These data are compatible S MALCOLM* were on first trimester chorionic villus with the VHL gene functioning as a *Mothercare Department of Paediatric biopsy specimens and resulted in two recessive tumour suppressor gene. Genetics, Institute of Child prenatal exclusions and four non- Sporadic CHB and some RCC may Health, London; tDepartment exclusions. The remaining 44 tests arise from somatic mutations inacti- of Clinical Neurology, Institute were on adults, 19 of whom had a vating both alleles at the VHL locus. of Neurology, London; tHospital greatly increased risk and 25 a sub- Nacional Marques de Valdecilla, stantially decreased risk of inheriting Santander, Spain. the HD gene. Family structures in Scotland are suitable for testing about Molecular genetic studies of Early reports suggested that the disease 75% of would-be consultands, while Angelman's syndrome locus for HMSNI, the commonest type the new generation of DNA markers S MALCOLM*, T WEBBt, P RUTLAND*, of inherited neuropathy in the UK, makes virtually all cases informative. H R MIDDLETON-PRICE*, M E PEMBREY* might be on chromosome 1, near the However, even with closely linked *Mothercare Department ofPaediatric Duffy blood group locus. Subsequent markers, residual risks of HD in many Genetics, Institute of Child Health, work from many groups, including consultands are less than ideal. This London; tDepartment of Clinical copyright. ours, failed to confirm this, suggesting does not appear to deter those who Genetics, Birmingham Maternity that the earlier results arose by chance embark on predictive testing. Hospital. or that HMSNI is genetically hetero- geneous. Vance et al (Exp Neurol Thirty-seven typical cases of Angel- 1989;104:186-9) have reported linkage man's syndrome have been studied. of HMSNI to the pericentromeric Statistical analysis of the two stage Cytogenetic deletions in the region region of chromosome 17. We have mutation model in von Hippel-Lindau 15qIl-q13 were observed in 18/24 confirmed this linkage in eight families. isolated cases. No were disease, sporadic cerebeliar deletions http://jmg.bmj.com/ D17S58 (EW301) gave a maximum lod haemangioblastoma, and renal celi observed in 13 cases from six families score of 5-89 at 0=0-08 and D17S71 carcinoma with more than one affected child. (pA10-41) a maximum lod score of E R MAHER, J R W YATES, DNA probes from the region (D15S24 3-22 at 0=0-08. EW301 is on 17p, M A FERGUSON-SMITH and D15S13), which detect RFLPs, 5-5 cM from the centromere. One Cambridge University Department were used to confim the deletion in family, previously reported as showing ofPathology, Cambridge. four cases. In other deletion cases the linkage to the Duffy blood group locus same probes are present m two copies, on chromosome 1, was included in the Analysis of the age incidence curves for showliig variable deletion breakpoints. study and now provides a positive lod unilateral and bilateral retinoblastoma In 11 cases it has been possible to on October 1, 2021 by guest. Protected score for chromosome 17 markers (lod led Knudsen (Proc Natl Acad Sci USA elucidate the parental origin of the 1-80 at 0=0 D17S58). There was no 1971;68:820) to propose that hereditary deleted chromosome and these have evidence of heterogeneity. tumours may arise by a single event been shown to be predominantly of and sporadic tumours by a two stage maternal origin. Cytogenetics have mutation process. Recently Erlandssen shown a de novo deletion of a maternal et al (Cancer Genet Cytogenet 1988;36: chromosome in five cases and paternal Predictive testing for Huntington's 197) have suggested that sporadic renal in two. Molecular genetics have shown disease (HD) in Scotland: the first 50 cell carcinoma (RCC) arises from a two amaternal origin in fourcases(including cases stage mutation process. We analysed confirmation ofone cytogenetic result). D J H BROCK, M MENNIE, A CURTIS, the age incidence curves for symptom- Flow karyotyping has shown one F A MILLAN, L BARRON, J A RAEBURN, atic RCC (n=26) and cerebellar maternal deletion. This is in contrast D DINWOODIE, S HOLLOWAY, A CROSBIE, haemangioblastoma (CHB) (n=68) in to the overwhelmingly paternal origin A WRIGHT, I PULLEN 109 patients with VHL disease, and of an apparently similar deletion Human Genetics Unit, University of compared them to 104 patients with in Prader-Willi syndrome. Linkage Edinburgh, Edinburgh. sporadic RCC and 43 patients with studies in affected sibs make straight- sporadic CHB. The age incidence forward autosomal recessive inheri- Using DNA probes at the D4S10, curves for RCC and CHB in VHL tance unlikely. 206 Clinical Genetics Society J Med Genet: first published as 10.1136/jmg.27.3.205 on 1 March 1990. Downloaded from

Lethal osteogenesis imperfecta: The results of X chromosome RFLP A genetic study of ataxia a family with 6 affected sibs studies undertaken on a 36 year old telangiectasia: what benefit heterozygous for a type I coliagen male with the 49,XXXXY syndrome to the families? mutation are presented. Chromosome analysis C G WOODS, S BUNDEY S C M DAW*, D A GIBBS*, A C NICHOLLS*, from cultured lymphocytes showed a Department of Clinical Genetics, E C HALLt, D C SIGGERSt, F M POPE* 49,XXXXY constitution in 45 (90%) Birmingham Maternity Hospital, *Dermatology Research Group, out of 50 cells examined, with a Edgbaston, Birmingham B15 2TG. MRC Clinical Research Centre, 48,XXXY constitution in the remain- Watford Road, Harrow, Middlesex ing five (10%) cells. Parental chromo- A genetic study of families with ataxia HAI 3U7; tRoyal United Hospital, somes were normal. X chromosome telangiectasia in the UK was con- Bath, Avon. RFLP analysis using the pERT87-1 ducted. We were interested to know and 87-15 probes with XmnI enzyme why families had participated and if We describe a family with unrelated, indicated that all of the patient's X they had found the study of any help. normal parents in which six preg- chromosomes were maternally derived Fifty-two families were contacted by nancies have been affected with thin and that he possessed two copies of letter, introducing the genetic study. boned osteogenesis imperfecta (01). each of his mother's pERT alleles. Four did not respond, one declined to There have been no normal children. participate, and 47 agreed and were The first affected infant, delivered at Tay-Sachs disease heterozygote subsequently visited at home. When 39 weeks' gestation, died after 10 screening visited almost all families spoke of hours. The index case and two other I H ELLIS, A H FENSOM, E C GUEST, isolation, rarely knowing another pregnancies were terminated after A OLADIMEJI, M BOBROW affected family. After completion of ultrasound diagnosis. Histological and Paediatric Research Unit, Division of the genetic study an anonymous radiological findings confirmed 01. Medical and Molecular Genetics, questionnairewassent tothe47families: Skin fibroblast cell lines were establish- UMDS, Guy's Hospital, London 43 replied. Most had participated ed from the index case and from both SE] 9RT. because "it would help in the future". parents. Collagen was metabolically None objected to blood samples being labelled in cell culture and analysed Carriers of the Tay-Sachs disease taken from all family members. All by SDS-PAGE. The index fetus (TSD) gene have a reduced percentage wanted to know study results. Two synthesised and secreted overmodified of hexosaminidase A (Hex A), which families, who were put in touch during type I collagen. The use of a a'- can be differentiated from the other the study, started an ataxia telangiec- copyright. dipyridyl and one dimensional cyano- Hex isoenzymes by its relative lability. tasia parents support group. In human gen bromide peptide mapping showed We have developed an automated assay terms, this genetic study of a rare excessive post-translational hydroxy- for Hex A using a centrifugal analyser. disorder was of great benefit to the lation throughout the triple helical After a manual heat inactivation step, families involved. portion of the molecule. However, Hex A levels are measured in serum. once formed, the collagen melted at the Assay on leucocytes is used to follow normal temperature. Protein from the up positive or borderline serum results Strategies for detection of single base parents appeared normal. The pre- in and when serum results are unreliable, changes subjects heterozygous http://jmg.bmj.com/ sence of overhydroxylated a chains especially during pregnancy. The for alleles of the apolipoprotein B was also shown in cells taken by advantage of the centrifugal analyser gene chorionic villus biopsy from a sub- over continuous flow systems in ALISON M DUNNING, sequent pregnancy. Ultrasonography current use is its relative simplicity of LINDA KING-UNDERWOOD, confirmed the diagnosis of an affected operation and its versatility in also RICHARD HOULSTON, PHILIPPA J fetus, which was then terminated. The handling leucocyte samples, as we TALMUD, STEVE E HUMPHRIES biochemical profiles of these two receive many samples from antenatal Charing Cross Sunley Research Centre, affected subjects were identical. Two clinics. We have defined our normal Arterial Diseases Research Group, dimensional cyanogen bromide peptide range from testing the sera of 30 Lurgan Avenue, Hammersmith, London on October 1, 2021 by guest. Protected mapping has now indicated that both obligate TSD carriers and 184 non- W6 8LW. the affected fetuses are heterozygous. Jewish blood donors using 4-MU-- We suggest that the mutation is N-acetylglucosaminide as substrate. Apolipoprotein B (apo B) is the sole dominant and that it may illustrate Four per cent of people initially tested apoprotein on the low density lipo- gonadal mosaicism. on serum give borderline results which protein (LDL) particle and the ligand can be resolved on leucocyte testing. through which this particle is cleared Use of the highly Hex A specific via the LDL receptor. As such, apo B POSTERS substrate 4-MU-43-GlcNAc--6-sul- plays a central role in cholesterol meta- phate avoids the need for the three bolism and thus the apo B gene is a Origin of the X chromosome hour heat inactivation step and candidate for the development of in a patient with the 49,XXXXY provides better discrimination when atherosclerosis. It has been shown that syndrome the data are analysed as a two dimen- several subjects have reduced clearance D S PLAHA*, D P DUCKETTt, sional plot of Hex A versus Hex A/total rates of LDL cholesterol that are not R A COLLACOT4, I D YOUNG* Hex. The data we have obtained from the result of defects in the LDL Departments of Child Health*, screening 2556 members of the Jewish receptor. We have been developing Cytogeneticst, and Psychiatry*, community in Britain so far indicate a PCR related techniques of direct Leicester Royal Infimarym, Leicester. carrier frequency of 1 in 27. sequencing, mismatch analysis, and Clinical Genetics Society 207 J Med Genet: first published as 10.1136/jmg.27.3.205 on 1 March 1990. Downloaded from

allele specific oligo (ASO) melting, in diagnosis feasible. We report three equilibrium with the cystic fibrosis order to detect mutations affecting the years' service experience of providing (CF) mutation on chromosome 7. Our putative receptor binding domain of presymptomatic detection and prenatal data show that in Welsh families, CF apo B, which may be the cause of the diagnosis for myotonic dystrophy in 99 segregates predominantly (85 3%) with reduced clearance. families. Careful clinical study of older haplotype B (pXV2c allele I/pKM19 family members remains important. allele 2) whereas this haplotype occurs The introduction of new probes in only 11-4% of normal chromosomes. Use ofPCRtogenotype apolymorphic (CKMM and BCL4) has helped to Based on this information we have dinucleotide repeat within the solve the problem ofuninformativeness beenable to helpfamilies wherematerial PAI-i gene in patients with a owing to unhelpful genotype distri- from an index case is not available for recent MI bution in a family. Nevertheless DNA analysis; we have also adjusted S J DAWSON*, A M HENNEY*, informativeness cannot be guaranteed the risks ofcarrier status for partners of S HUMPHRIES*, A HAMSTENt and families should be studied before CF patients and for partners of known *Charing Cross Sunley Research Centre, pregnancy is undertaken whenever CF carriers. In addition knowledge of Lurgan Avenue, London W6 8LW; possible. Presymptomatic testing and haplotypes may be used to strengthen tKarolinska Institute, King Gustaf V prenatal diagnosis for myotonic or weaken a possible diagnosis of CF: Research Institute, Stockholm, Sweden. dystrophy are soundly based. All these situations have arisen when affected subjects should have DNA diagnostic criteria have been border- Plasminogen activator inhibitor (PAI banked for future use when other line, or when the death of an infant -1) has been identified as an inde- family members may require genotype with suggestive symptoms has oc- pendent risk factor for myocardial information. curred early in the neonatal period infarction (MI). An eight allele di- before a confirmatory sweat test can be nucleotide CA repeat polymorphism Lethal bowing syndrome in two sibs carried out. was identified within the PAI-I gene R SALONEN, H AHO, J SPRANGER using PCR. Allele frequencies were Laboratory ofPrenatal Genetics, estimated in 44 random subjects and Department of Obstetrics and ranged from Cystic fibrosis DNA probe 0-02 to 0-37. Inheritance Gynaecology, Helsinki University anomalies: crossover, misdiaosis, was followed in an extended family and Central Hospital, Finland. was non-paternity or sample error according to Mendelian rules. C A A M N GRAHAM, J HILL, C NEVIN copyright. Genotypes were determined for two Two sibs with skeletal changes similar Department ofMedical Genetics, populations: one healthy and one of to a patient reported by R E Stevenson Queen's University ofBelfast, patients with a recent MI. These data (Proc Greenwood Center 1982;1:47) are Belfast. were compared with similar experi- presented. The first affected female ments with a previously reported child of the family was born at 33 During the routine DNA analysis of 83 HindIII RFLP using standard weeks of pregnancy. She had very Southern blotting cystic fibrosis families in Northern techniques. The short, curved limbs with flexion Ireland, we identified four families in HindIII 2-2 genotype was significantly contractures in the arms, club feet, which there to have associated with raised PAI levels in the appeared been one, small chin, low set ears, and dimples or more, recombination events http://jmg.bmj.com/ control population and the same on the knees and buttocks. The radio- between the association was found in the probes Met H, Xv-2c, patient graphs showed sharply angulated radii, KM19, or pJ3.11 and the CF gene. population but at a non-significant ulnae, femora, tibiae, and fibulae. The The affected subjects had been level. The HindIII and CA repeat child died of respiratory difficulties diagnosed either by increased levels of genotypes arein linkage disequilibrium. after 10 hours. No additional abnor- Routine use of PCR to type immunoreactive trypsin and sweat these malities were found at necropsy. After testing or by sweat testing alone after highly informative polymorphic di- the birth of a normal child fetal death referral on clinical nucleotide repeats provides a rapid suspicion. Family 1 was found by ultrasound at 15 weeks of (three affected) showed an apparent method for following the inheritance of the following pregnancy. The male on October 1, 2021 by guest. Protected genetic markers. crossover with Xv-2c but on further fetus had skeletal changes identical to investigation a diagnosis of ectopic the first affected child. This suggests eczema was made. The affected subject Presymptomatic detection and autosomal recessive inheritance of this from family 2 showed several anomalies prenatal diagnosis for myotonic condition. with the probes Xv-2c and Met H and, dystrophy by means of linked DNA when examined with the VNTR probe markers Clinical application of haplotype YNH24, appeared to have no maternal A M NORMAN, J L FLOYD, A L MEREDITH, frequencies in cystic fibrosis alleles. The results did suggest, how- P S HARPER families in Wales ever, that the samples from the affected Institute ofMedical Genetics, L AL-JADER*, L MEREDITH*, girl and her father had been mixed up University of Wales College M SARFARAZI*, M GOODCHILDt, and this was confirmed using an X ofMedicine, Heath Park, R PROSSER , P S HARPER* linked VNTR probe M27. Both family Cardiff CF4 4XN. *Institute ofMedical Genetics, UHW; 3 (two affected, one unaffected) and fDepartment of Child Health, UHW; family 4 (four affected, two unaffected) The close genetic linkage between the fRoyal Gwent Hospital, Wales. showed a potential crossover between loci for apolipoprotein CII (apo CII) KM19 and CF with no evidence of and myotonic dystrophy makes pre- The DNA markers pXV2c and non-paternity or misdiagnosis. Family symptomatic detection and prenatal pKMl9 show strong linkage dis- 5 (two affected) showed multiple cross- 208 Clinical Genetics Society J Med Genet: first published as 10.1136/jmg.27.3.205 on 1 March 1990. Downloaded from overs including Xv-2c, KMl9, and hypertelorism; micrognathia with class The genetic distance of F8 from pJ3. l1. Testing with the VNTR II occlusion in the mother; high palate; FRAXA remains undetermined and probes did not suggest sample error or and relative short stature (10th centile). pulse field gel electrophoresis data non-paternity and the diagnosis of CF The mother is of normal intelligence (Patterson et al, 1987) showing its was confirmed. Further analysis of and her daughter is making normal proximity to G6PD rather than to the these families with the probes D9 and developmental progress. The mother's cluster (DXS52, DXS15) suggested C67 will be necessary. parents and her other child have that it should be investigated as a normal karyotypes and no craniofacial potential flanking marker for carrier abnormalities. Chromosome abnormal- detection in the fragile X syndrome. A molecular study to identify ities have not previously been Families segregating for fragile X a subject homozygous for the reported in cleidocranial dysostosis, syndrome were studied with an in- myotonic dystrophy gene although the dysmorphic features formative intragenic F8 polymorphism HELEN G HARLEYk, J DAVID BROOK*, present in this family may represent a but a peak lod score of 0-63 at 0=0-27 DUNCAN J SHAW*, PETER S HARPER", new clinical entity. The presence of the suggested insufficient meioses had ELIZABETH j IVESt chromosomal translocation in the been available to estimate the precise .'Institute ofMedical Genetics, affected mother and daughter suggest recombination fraction. A multipoint University of Wales College ofMedicine, localisation of a dominant gene causing linkage analysis using the LINKMALP Heath Park, Cardiff; fMemorial cleidocraniofacial abnormalities at component of LINKAGE 4-7 excluded University of Newfoundland, either 8q22.3 or l0pl3. FRAXA from the interval DXS52-F8 St3John's, Newfoundland, Canada. with a peak lod score of -2-0 being observed for that test interval. A multi- We have studied a large multigenera- Types of albinism in the Black ply informative phase known family tional pedigree in which two third populations of Southern Africa supports the order in distal Xq cousins, both affected with myotonic J G R KROMBERG, E ZWANE, T JENKINS of: FRAXA-(DXS52, DXS15, probe dystrophy (DM), have married. They MRC Human Ecogenetics Research lA1)-F8-telomere. Thus in the fam- have four children who are affected Unit, SAIMR and University of the ilies studied F8 appears to be too with DM, and are therefore possibly Witwatersrand, Johannesburg, South loosely linked to be a useful flanking homozygous at the DM locus. All four Africa. marker in fragile X syndrome and is children have been examined by one of likely to be the most telomeric of the copyright. us (EJI) and a clinical summary will be Oculocutaneous albinism (OCA) distal interval markers used. presented. We have used the poly- occurs in 1 in 3900 births in Southern morphic DNA probes BCL3, APOC2i Africa. This study aimed to identify and CKMM, shown to be within 2 cM and describe the local types of OCA. Prenatal diagnosis of the fragile X of the DM gene, as well as some Subjects were ascertained during a syndrome recently isolated probes, also closely community survey and types were T WEBB linked to DM, in order to follow the identified by clinical examination, hair Department of Clinical Genetics, inheritance of the DM haplotype in the bulb incubation tests, tyrosinase (ty) Birmingham Maternity Hospital, assays, and visual evoked potential Binningham B15 2TG. family. This information has been used Edgbaston, http://jmg.bmj.com/ to determine if any of the four subjects testing. Results showed that in 96 in question is homozygous at the DM albinos 82% had ty-pos OCA, 11-5% Prenatal diagnosis has been undertaken locus and to determine if severity of the brown, and 6% rufous albinism. None for 50 pregnancies in women who are at DM phenotype is subject to a dosage had ty-neg albinism (mapped to 1 1q1 1) risk for the fragile-X or Martin-Bell effect. or the allelic yellow mutant type. The syndrome. Owing to the invasive ty-pos subjects comprised both those nature of the procedure, the majority with pigmented patches and those of pregnancies undergoing cordo- Chromosomal translocation t(8;10) without, the latter being at significantly centesis had been previously selected as (q22.3;p13) associated with greater risk for skin cancer. The brown male, either by CVS or ultrasound. Of on October 1, 2021 by guest. Protected dominantly transmitted cleidocranio- albinos had more pigment than the ty- the 50 mothers, 34 were considered to facial abnormalities pos and fewer visual problems. The be carriers of the syndrome either K OCRAFT, A REEVE, H M KINGSTON rufous had the most pigment and the because they themselves carried the Tameside General Hospital, least visual problems. The decussation fragile X (26 subjects) or because they Ashton-under-Lyne; Department defect of the optic tract detected in had a previous affected child (18 ofMedical Genetics, St Mary's Hospital, three ty-pos albinos was not apparent subjects) or both. There were 43 male Manchester. in three rufous subjects. Homogeneous outcomes of which 11 were positive for OCA groups have to be identified the fragile X. Of these, nine were An apparently balanced translocation, before results from molecular studies terminated and two were liveborn. 46,XX,t(8;10)(q22.3;p13) was detected can be interpreted. (One was missed prenatally and the in a mother and daughter who other mother refused a termination.) presented with identical craniofacial Linkage study of F8 in the fragile X Seven female pregnancies resulted in abnormalities. The dysmorphic fea- syndrome two fragile X positive (one terminated, tures consisted of hypoplastic clavicles; I A GLASS, E M WHITE, L A PIRRIT, one liveborn) and five fragile X negative large anterior fontanelle in the daughter M V BELL, J M CONNOR outcomes. Of the 23 fragile X positive with suggestion of wormian bones on University Department ofMedical mothers with male pregnancies, 14 had skull x ray; broad forehead; marked Genetics, Yorkhill, Glasgow G3 8SJ. boys without fragile X, while nine J Med Genet: first published as 10.1136/jmg.27.3.205 on 1 March 1990. Downloaded from Clinical Genetics Society 209

males were fragile X positive showing between OTC and M27f3. This enabled families, in which a new mutation is an expected deficiency. Recently, early flanking markers to be used for the identified in the middle generation. We detection of the fragile X in CVS detection of female carriers in this have analysed five families with 12 sampleshas resulted in theidentification family. In none of the females was a chromosome 17 DNA markers and the of two affected pregnancies obviating tapetal reflex (metallic sheen) observed, new mutation is of paternal origin. It the need for fetal blood sampling. suggesting that this phenotypic feature has been possible to infer the chromo- is not a reliable marker for mutations at some on which the new mutation the more distal RP2a locus. originated from the haplotypes in each Clinical problems associated family. Paternity was confirmed in with predictive testing for each family using hypervariable DNA Huntington's disease Linkage of Watson's syndrome probes. NFI resembles retinoblastoma M MORRIS, A TYLER, L LAZAROU, to chromosome 17 markers in that both show a predominance of L MEREDITH, P S HARPER MEENA UPADHYAYA, paternal new mutation but little or no Institute ofMedical Genetics, MANSOOR SARFARAZI, S HUSON, paternal age effects. University of Wales College ofMedicine, W BROADHEAD, J ALLANSON, Cardiff CF4 4XN. A FRYER, P S HARPER *Institute ofMedical Genetics, Identification of candidate genes Experience with nearly 300 applicants University of Wales College ofMedicine, for cardiac malformations for predictive testing for Huntington's Heath Park, Cardiff CF4 4XN. using RNA from first trimester disease has shown that apart from the human hearts expected problems, such as those Watson's syndrome was first reported P BRENNAN*, K DUFFt, S-J RICHARDSt, related to possible misuse of the test, in 1967 and is characterised by cafe au D J PRITCHARD*, J BURN* there were several less foreseen diffi- lait spots, freckling, pulmonary *Department of Human Genetics, culties. These may be divided into stenosis, and short stature. We have University ofNewcastle upon Tyne; those occurring before, during, and analysed a three generation family tDepartment ofBiochemistry after the test. Examples of problems with Watson's syndrome using and Molecular Genetics, St Mary's occurring before testing are inappro- 12 chromosome 17 pericentromeric Hospital Medical School, priate referrals, lack of clear family markers, of which eight were informa- London W2 (now at: MRC Molecular history, and counselling of the affected tive. Close linkage with DNA marker Genetics Unit, Addeizbrooke's Hospital, copyright. applicant and the applicant with D17S33 was noted (H=0-00, Z=3 20). Cambridge). equivocal symptoms. Problems during This marker is also the closest marker testing concern collection of blood to NFI. Watson's syndrome may be The complex congenital cardiac mal- samples (inadequate labelling, use of allelic to NF1. Linkage analysis for formation 'atrioventricular septal de- pseudonyms) and unintentional risk other variant forms of NF and for fect' shows a strong association with alteration. Problems after testing pulmonary stenosis is indicated. human trisomy 21 and murine trisomy include requests from third parties for 16 (the genetic homologue of Down's results of the test and refusal of follow syndrome). In addition, Mendelian

up by applicants. More of the problems Paternal origin of new mutation inheritance of the defect has been http://jmg.bmj.com/ involve clinical and counselling aspects in Von Recklinghausen reported in several pedigrees. It was rather than laboratory procedures. neurofibromatosis (NFI) therefore hypothesised that the in- M UPADHYAYA, A FRYER, herited genetic lesion in these families W BROADHEAD, S HUSON, P S HARPER involves a gene which maps in the X linked retinitis pigmentosa: Institute ofMedical Genetics, Down's syndrome region of chromo- recombinational analysis and carrier University of Wales College of some 21 and plays an important role in estimation with the proximal Medicine, Heath Park, Cardiff the process of atrioventricular sep- Xp markers XJ1.1, OTC, and M27, CF4 4XN. tatiof. To isolate possible chromo- C A GRAHAM*, R M REDMONDt, some 21 specific candidate genes, RNA on October 1, 2021 by guest. Protected D B ARCHERt, N C NEVIN* Von Recklinghausen neurofibroma- was extracted from 61 human em- *Department ofMedical Genetics, tosis is one of the most frequent auto- bryonic and early fetal hearts obtained The Queen's University, Belfast; somal dominant disorders with a pre- from the products of 109 routine tDepartment of Ophthalmology, valence of about 1 in 5000. The suction terminations of pregnancy. The Queen's University, Belfast. mutation rate is very high and about Total RNA preparations were electro- 50/o of affected cases result from a new phoresed in agarose gels containing X linked retinitis pigmentosa (RP2) is a mutation. Linkage analysis has formaldehyde and transferred to nitro- hereditary retinal degenerative dis- recently mapped the disease to cellulose membranes by northern order which has been localised to the chromosome 17 and the identification blotting. DNA sequences previously proximal short arm of the X chromo- of two NFl patients with balanced isolated from the Down's syndrome some. Recent evidence suggests that translocations has allowed the location region of chromosome 21 were radio- the disorder is heterogeneous with two of the disease to be narrowed to labelled and used as gene probes for possible loci for the, disease mutation. 17qll.2. With the availability of the specific mRNAs. Of 13 sequences Recombinations observed on DNA closely linked DNA markers to NFl, it tested, four were found to be expressed analysis of the family presented in this is now possible to determine directly in early cardiac tissue. This study paper show that the mutation is the parental origin of new mutation by provides four candidate sequences mapped to the more distal loci (RP2a), genetic linkage in three generation which can be used to analyse possible J Med Genet: first published as 10.1136/jmg.27.3.205 on 1 March 1990. Downloaded from 210 Clinical Genetics Society cosegregation of particular restriction The mutation causing cystic fibrosis separated using PFGE. Preliminary fragment length polymorphisms with (CF) has been characterised and carrier data show that DNA probes close to the defect in a number of pedigrees. testing in the general population will Xq27.3 detect different sized frag- Such an approach may permit the now be possible. A survey has been ments in fragile X and normal cell aetiology and pathogenesis of familial undertaken in north west London to lines. This suggests that this method atrioventricular septal defect to be assess knowledge of cystic fibrosis and of using chemical and enzymatic determined by identifying the under- attitudes to carrier screening and to probes may help gain an insight into lying gene defect. ascertain what the demand for such a the structure of the region. service will be. The survey has shown considerable interest from the general The use of 'ARMS' primers for public, with most people indicating the detection of the mutation they would like to know their carrier Linkage markers in schizophrenia causing cystic fibrosis and a rapid status. CF relatives have expressed in Wales and simple technique for very strong feelings that screening MATTHEW SERGEANT, PETER McGUFFIN, paternity testing should be introduced. General prac- GILLIAN HErr, ROGER MARCHBANKS, CAROLYN WILLIAMS, EDWARD MAYAL, titioners and medical staff at Family STEPHEN WHATELY BOB WILLIAMSON Planning Clinics within North West Department of Psychological Medicine, North West Thames Regional Thames Regional Health Authority University of Wales College ofMedicine, DNA Laboratory, Department of have also indicated that they believe Cardiff; Department of Biochemistry, Biochemistry and Molecular carrier testing for CF would be a Institute of Psychiatry, London. Genetics, Imperial College, worthwhile exercise. Possible strategies London W2 IPG. for the introduction of screening within Large or moderately large pedigrees the NHS have been explored. containing multiple family members Until recently cystic fibrosis (CF) affected by schizophrenia have been carrier testing has been perforrned sought throughout Wales. All available using linkage disequilibrium data family members from pedigrees with a generated from haplotype data potentially informative structure have obtained using closely linked probes. Structural studies of the fragile site been interviewed using the Past

Useful sequence data from these at Xq27.3 History Schedule (PHS) (McGuffin et copyright. probes have made it possible for the R G DEL MASTRO, M W KILPATRICK al, 1986) and an augmented version of majority of haplotypes to be generated University of Birmingham, Department the PSE (Wing et al, 1974). Additional using polymerase chain reaction. The of Clinical Genetics, Birmingham information has been collected using mutation causing cystic fibrosis has Maternity Hospital, Birmingham the Operational Criteria Checklist for now been cloned and sequenced, B15 2TG. Psychotic Illness (OCCPI). Several enabling the precise detection of the DNA markers are being studied; most common CF abnormality. Three Very little is known of the structure of however, for the purposes of this brief methods for the detection of the the fragile sites on chromosomes at the report we will focus on the 5qll-13 mutation are being developed in our molecular level. A common form of region where linkage to a putative http://jmg.bmj.com/ laboratory: looking directly at the mental retardation (Martin-Bell syn- schizophrenia susceptibility gene has mutation on a polyacrylamide gel; drome) is frequently associated with a been reported and we will present data using radioactive allele specific oligo- fragile site at Xq27.3. There are many on six pedigrees. We applied a 'near nucleotides; using primer sequences theories as to the structure of this dominant' model of schizophrenia specific for the presence and absence of region at the DNA level, but little transmission as in the published report the mutation. It is now possible to experimental evidence. Cytogeneti- of Sherrington et al (1988), with some detect the three base pair deletion cally, the fragile site appears not to minor modifications. Two point using alternative primers, reading in have condensed properly. Using fragile linkage analysis with plO5-599Ha different directions from the mutation. X and normal cell lines, chemical and excluded close linkage. Although four on October 1, 2021 by guest. Protected enzymatic probes (which detect struc- families showed weakly positive lod tural perturbations in the DNA) have scores with plO5-153R, on carrying Community attitudes to carrier been used to investigate the structure out multipoint analysis with schizo- screening for cystic fibrosis of the DNA in the region of the fragile phrenia as the test locus and the two E WATSON, J CHAPPLE, R WILLIAMSON site. Following treatment with the markers fixed at approximately 16 cM Department of Biochemistry and structural probe and removal of apart, we found that a gene for schizo- Molecular Genetics, St Mary's Hospital histones, the DNA was digested with phrenia in this region in our Welsh Medical School, London W2 IPG. rare cutting enzymes and the fragments pedigrees is improbable.