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.