Clinical Genetics 1987: 31: 4-7

Prenatal diagnosis in Becker muscular dystrophy

STEPHEN WOOD!, ROBERT J. SHUKIN~, Siu LI YONG!, DOUG WILSON~,', DAGMAR KALOUSEK~.~ AND

Departments of !Medical Genetics, 'Obstetrics, and 3Pathology, University of British Colombia, Vancouver, B. C., and 'Section of Clinical Genetics, Children's Hospital, Winnipeg, Manitoba. Canada

ALBERT CHUDLEY4

Prenatal diagnosis in a pregnancy at risk for Becker muscular dystrophy is reported. The diagnosis was made prior to 12 weeks of gestation by typing a CVS sample for DNA markers.

Received 21 July, accepted for publication 23 Ju1.v 1986

Key words: Becker muscular dystrophy; chorionic villus; DNA markers; prenatal diagnosis.

The practical use of linked restriction frag- ment length polymorphisms (RFLPs) for carrier detection and prenatal diagnosis of Duchenne muscular dystrophy (DMD) has recently been reported (Bakker et al. 1985). These same DNA probes are of equal value in families with Becker muscular dystrophy (BMD) since recent linkage data (Kingston et al. 1983, Wilcox et al. 1985, Brown et al. 1985) is compatible with DMD and BMD being allelic disorders. DNA probes have now been isolated that appear to lie within the Duchenne gene itself (Monaco et al. 1985, Ray et al. 1985) and RFLPs detected by these probes show infrequent recombina- tion with Duchenne mutations. Conse- quently, until practical methods become available for the detection of either specific mutations or of gene function, these closely linked RFLPs will remain valuable for as- sessing segregation in families at risk for both DMD and BMD.

Material and Methods

Case Report Our patient (Figure I , individual 4) presen-

ted at 8 weeks of gestation. Her only brother had BMD, presenting at the age of 2 with muscle weakness and hypertrophy of the calf muscles. A diagnosis of DMD was made at the age of 12 on the basis of clinical findings, serum creatinine phosphokinase levels and muscle biopsy. Presently, at the age of 31, he has been confined to a wheel- chair for 6 years and his status is consistent with BMD. The family history is otherwise uninformative.

Laboratory Investigations We initially typed our patient, her brother and their parents for 4 RFLPs in the p87 region (Monaco et al. 1985) and the close flanking 99.6 and 754 markers (Bakker et al. 1985). Three p87 markers and 754 were informative and indicated that our patient and her brother had received the same mar- kers from their mother and thus the preg- nancy was at risk. Consequently at a gesta- tional age of 10 weeks and 4 days from LMP we obtained a 30 mg chorionic villus sample (CVS) for cytogenetic analysis and DNA typing, together with a blood sample

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from the patient's husband for DNA typ- ing. Cytogenetic analysis indicated a female fetus. This was confirmed by DNA analysis which also showed that the fetus did not inherit the markers that her mother shared with the affected brother (Figure 1). Thus it became unlikely that the fetus was a carri- er of BMD.

Discussion

We have estimated risks in the following way. Using 18u (Emery 1983) as the apriori female carrier risk for BMD, the a posteriori risk that our patient's mother is a carrier is 90%. This differs from the 2/3 risk of being a DMD camer in a similar pedigree because of the greater genetic fitness of BMD pati- ents. The markers we tested may segregate from the BMD mutation due to a double crossing-over between p87 and 754 if the mutation is proximally located or a single crossover if the mutation is distally located. These recombination frequencies are likely to be in the range of 1 % to 4%. Thus we calculate the carrier risk for our patient at 83% to 88% and for her fetus as 3.3% to 0.9%. Segregation studies based on linked

References

Bakker, E., M. H. Hofker, N. Goor, J. L. Mandel, K. Wrogemann, K. E. Davies, L. M. Kunkel, H. F. Willard, W. A. Fenton, L. Sandkuyl, D. Majoor-Krakauer, A. J. V. Essen, M. G. J. Jahoda, E. S. Sachs, G. J. B. van Ommen & P. L. Pearson (1985). Prenatal diagnosis and camer detection of Duchenne muscular dystro- phy with closely linked RFLPs. Lancer i, 655-658.

Brown, C. S., N. S . T. Thomas, M. Safarazi, K. E. Davies, L. Kunkel, P. L. Pearson, H. M. Kingston, D. J. Shaw & P. S. Harper (1985). Genetic linkage relationship of seven DNA probes with Duchenne and Becker muscular dystrophy. Hum. Genet. 71, 62-14.

Emery, A. E. H. (1983). The muscular dystro- phies. In Principles and Practice of Medical Genetics. A. E. H. Emery & D. L. Rimoin (eds). Edinburgh, Churchill Livingstone, pp. 392-4 1 3.

Kingston, H. M., P. S. Harper, P. L. Pearson, K. E. Davies, R. Williamson & D. Page (1983). Localisation of gene for Becker muscular dy- strophy. Lancet ii, 1200.

Monaco, A. P., C. J. Bertelson, W. Middlesworth, C-A. Colletti, J. Aldrige, K. H. Fischbeck, R. BartIett, M. A. Pericak-Vance, A. D. Roses & L. M. Kunkel, L. M. (1985). Detection of dele- tions spanning the Duchenne muscular dystro- phy locus using a tightly linked DNA segment. Nature 316, 842-845.

Ray, P. N., B. Belfall, C. Duff, C. Logan, V. Kean, M. W. Thompson, J. E. Sylvester, J. L. Gorski, R. D. Schmickel & R. G. Worton

P R E N A T A L D I A G N O S I S I N B M D

(1985). Cloning of the breakDoint of an X:21 Address: - translocation associated with Duchenne mu- Dr. Wood scular dystrophy. Nature 318, 672675.

Wilcox, D. E., N. A. Affara, J. R. W. Yates, M. A. Ferguson-Smith & P. L. Pearson (1985). Multipoint linkage analysis of the short arm of the human X chromosome in families with X-linked muscular dystrophy. Hum. Genet. 70, 365-375.

Department of Medical Genetics university of British Colwnbia 6174 universiry

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