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Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study

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Summary

Knowledge about the parental origin of new mutations and the occurrence of germline mosaicism is important for estimating recurrence risks in Duchenne (DMD) and Becker muscular dystrophy (BMD). However, there are problems in resolving these issues partly because not all mutations can as yet be directly detected, and additionally because genetic ratios are very sensitive to ascertainment bias. In the present study, therefore, analysis was restricted to currently detectable mutations (deletions and duplications) in particular types of families which tend to be rare. In order to obtain sufficient data we pooled results from 25 European centers. In mothers of affected patients who were the first in their family with a dystrophin gene deletion or duplication, the ratio between the paternal and the maternal origin of this new mutation was 32:49 (binomial test P = 0.075) for DMD. In five BMD families the ratio between paternal and maternal origin of new mutations was 3∶2. Recurrence risk because of maternal germline mosaicism was studied in sisters or subsequent sibs of isolated cases with an apparently new detectable mutation. In 12 out of 59 (0.20; 95% CI 0.10–0.31) transmissions of the risk haplotype the DMD mutation was transmitted as well. No recurrences were found in nine BMD families.

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References

  • Bakker E, Pearson PL (1986) Mutation of the Duchenne muscular dystrophy gene associated with meiotic recombination. Clin Genet 30:347–349

    Google Scholar 

  • Bakker E, Hofker MH, Goor N, Mandel JL, Wrogemann K, Davies KE, Kunkel LM, Willard HF, Fenton WA, Sandkuyl L, Majoor-Krakauer D, Essen AJ van, Jahoda MGJ, Sachs ES, Ommen GJB van, Pearson PL (1985) Prenatal diagnosis and carrier detection of Duchenne muscular dystrophy with closely linked RFLPs. Lancet I:655–658

    Google Scholar 

  • Bakker E, Bonten EJ, De Lange LF, Veenema H, Majoor-Krakauer D, Hofker MH, Ommen GJB van, Pearson PL (1986) DNA probe analysis for carrier detection and prenatal diagnosis of Duchenne muscular dystrophy: a standard diagnostic procedure. J Med Genet 23:573–580

    Google Scholar 

  • Bakker E, Broeckhoven C van, Bonten EJ, Vooren MJ van de, Veenema H, Hul W van, Ommen GJB van, Vandenberghe A, Pearson PL (1987) Germline mosaicism and Duchenne muscular dystrophy mutations. Nature 329:554–556

    Google Scholar 

  • Bakker E, Bonten EJ, Veenema H, Dunnen JT den, Grootscholten PM, Ommen GJB van, Pearson PL (1989a) Prenatal dignosis of Duchenne muscular dystrophy: a three-year experience in a rapidly evolving field. J Inherited Metab Dis 12:174–190

    Google Scholar 

  • Bakker E, Veenema H, Dunnen JT den, Broeckhoven C van, Grootscholten PM, Bonten EJ, Ommen GJB van, Pearson PL (1989b) Germinal mosaicism increases the recurrence risk for “new” Duchenne muscular dystrophy mutations. J Med Genet 26:553–559

    Google Scholar 

  • Barbujani G, Russo A, Danieli GA, Spiegler AW, Borkowska J, Hausmanova Petrusewicz I (1990) Segregation analysis of 1885 DMD families: significant departure from the expected proportion of sporadic cases. Hum Genet 84:522–526

    Google Scholar 

  • Bech-Hansen NT, Starozik DM, Dimnik L, Hoar DI, Meschino W (1987) Interstitial deletion and male-gonadal mosaicism as the basis for Duchenne muscular dystrophy. Am J Hum Genet 41:A93

    Google Scholar 

  • Bobrow M, Walker A, Walton J (1988) The parental origin of mutations causing Duchenne muscular dystrophy. Arch Neurol 45:85–87

    Google Scholar 

  • Boileau C, Junien C (1989) Misdiagnosed normal fetus owing to undetected germinal mosaicism for DMD deletion. J Med Genet 26:790–791

    Google Scholar 

  • Bröcker-Vriends AH, Rosendaal FR, Houwelingen JC van, Bakker E, Ommen GJB van, Kamp JJP van de, Briet E (1991) Sex ratio of the mutation frequencies in hemophilia A: coagulation assays and RFLP analysis. J Med Genet 28:672–680

    Google Scholar 

  • Bucher K, Ionasescu V, Hanson J (1980) Frequency of new mutants among boys with Duchenne muscular dystrophy. Am J Med Genet 7:27–34

    Google Scholar 

  • Bushby KMD, Thambyayah M, Gardner-Medwin D (1991) Prevalence and incidence of Becker muscular dystrophy. Lancet 337:1022–1024

    Google Scholar 

  • Claustres M, Kjellberg P, Desgeorges M, Bellet H, Demaille J (1990) Germinal mosaicism from grand-paternal origin in a family with Duchenne muscular dystrophy. Hum Genet 86:241–243

    Google Scholar 

  • Cooke A, Lanyon WG, Wilcox DE, Dornan ES, Kataki A, Gillard EF, McWhinnie AJ, Morris A, Ferguson-Smith MA, Connor JM (1990) Analysis of Scottish Duchenne and Becker muscular dystrophy families with dystrophin cDNA probes. J Med Genet 27:292–297

    Google Scholar 

  • Darras BT, Francke U (1987) A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male. Nature 329:556–558

    Google Scholar 

  • Darras BT, Blattner P, Harper JF, Spiro AJ, Alter S, Francke U (1988) Intragenic deletions in 21 Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) families studied with the dystrophin cDNA: location of breakpoints on HindIII and BglII exon-containing fragment maps, meiotic and mitotic origin of the mutations. Am J Hum Genet 43:620–629

    Google Scholar 

  • Dunnen JT den, Bakker E, Breteler EG, Pearson PL, Ommen GJB van (1987) Direct detection of more than 50% of the Duchenne muscular dystrophy mutations by field inversion gels. Nature 329:640–642

    Google Scholar 

  • Edwards JH (1986) The population genetics of Duchenne: natural and artificial selection in Duchenne muscular dystrophy. J Med Genet 23:521–530

    Google Scholar 

  • Emery AEH (1986) Methodology in medical genetics. Churchill Livingstone, Edinburgh

    Google Scholar 

  • Emery AEH (1988) Duchenne muscular dystrophy. Oxford Universtiy Press, Oxford

    Google Scholar 

  • Emery AEH, Skinner R (1976) Clinical studies in benign (Becker type) X-linked muscular dystrophy. Clin Genet 10:189–201

    Google Scholar 

  • Forrest SM, Cross GS, Speer A, Gardner-Medwin D, Burn J, Davies KE (1987) Preferential deletion of exons in Duchenne and Becker muscular dystrophies. Nature 329:638–640

    Google Scholar 

  • Francke U, Felsenstein J, Gartler SM, Migeon BR, Dancis J, Seegmiller JE, Bakay F, Nyhan WL (1976) The occurrence of new mutants in the X-linked Lesch-Nyhan disease. Am J Hum Genet 28:123–137

    Google Scholar 

  • Fu WM, Barbujani G (1990) Segregation and sporadic cases of Duchenne muscular dystrophy in the Henan Province, China. Hum Hered 40:167–172

    Google Scholar 

  • Grimm T, Danieli GA, Müller CR (1988) Theoretical expectations for deletional mutations in Duchenne muscular dystrophy. Am J Med Genet 29:445–451

    Google Scholar 

  • Grimm T, Müller B, Müller CR, Janka M (1990) Theoretical considerations on germline mosaicism in Duchenne muscular dystrophy. J Med Genet 27:683–687

    Google Scholar 

  • Hall JG (1988) Review and hypothesis: Somatic mosaicism: observations related to clinical genetics. Am J Hum Genet 43:355–363

    CAS  PubMed  Google Scholar 

  • Hoffman EP, Fischbeck KH, Brown RH, Johnson M, Medori R, Loike JD, Harris JB, Waterston R, Brooke MAUSL (1988) Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy. N Engl J Med 318:1363–1368

    Google Scholar 

  • Hu XY, Burghes AH, Bulman DE, Ray PN, Worton RG (1989) Evidence for mutation by unequal sister chromatid exchange in the Duchenne muscular dystrophy gene. Am J Hum Genet 44:855–863

    Google Scholar 

  • Karel ER, Meerman GJ te, Kate LP ten (1986) On the power to detect differences between male and female mutation rates for Duchenne muscular dystrophy, using classical segregation analysis and restriction fragment length polymorphisms. Am J Hum Genet 38:827–840 [published erratum appears in Am J Hum Genet (1987) 41:330

    Google Scholar 

  • Kate LP ten (1984) The significance of new mutations for the genetic epidemiology of Duchenne muscular dystrophy. In: Kate LP ten, Pearson PL, Stadhouders AM (eds) Research into the origin and treatment of muscular dystrophy. Excerpta Medica, Amsterdam, pp 3–6

    Google Scholar 

  • Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50:509–517

    Google Scholar 

  • Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Müller CR, Lindlöf M, Kääriäinen H, Chapelle A de la, Kiuru A, Savontaus ML, Gilgenkranz H, Recan D, Chelly E, Kaplan JC, Covone AE, Archidiacono N, Romeo G, Liechti-Gallati S, Schneider V, Braga S, Moser H, Darras BT, Murphy P, Francke U, Chen JD, Morgan G, Denton M, Greenberg CR, Wrogemann K, Blonden LAJ, Paassen HMB van, Ommen GJB van, Kunkel LM (1989) The molecular basis for Duchenne muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45:498–506

    CAS  PubMed  Google Scholar 

  • Lane RJ, Robinow M, Roses AD (1983) The genetic status of mothers of isolated cases of Duchenne muscular dystrophy. J Med Genet 20:1–11

    Google Scholar 

  • Lane RJ, Partridge T, Rose FC (1988) New mutations in Duchenne muscular dystrophy. Lancet II:971–972

    Google Scholar 

  • Lanman JTJ, Pericak-Vance MA, Bartlett RJ, Chen JC, Yamaoka L, Koh J, Speer MC, Hung WY, Roses AD (1987) Familial inheritance of a DXS164 deletion mutation from a heterozygous female. Am J Hum Genet 41:138–144

    Google Scholar 

  • Lebo RV, Olney RK, Golbus MS (1990) Somatic mosaicism at the Duchenne locus. Am J Med Genet 37:187–190

    Google Scholar 

  • Legius E, Baten E, Stul M, Marynen P, Cassiman J (1990) Sporadic late onset ornithine transcarbamylase deficiency in a boy with somatic mosaicism for an intragenic deletion. Clin Genet 38:155–159

    Google Scholar 

  • Liechti-Gallati S, Koenig M, Kunkel LM, Frey D, Boltshauser E, Schneider V, Braga S, Moser H (1989) Molecular deletion patterns in Duchenne and Becker type muscular dystrophy. Hum Genet 81:343–348

    Google Scholar 

  • Love DR, Davies KE (1989) Duchenne muscular dystrophy: the gene and the protein. Mol Biol Med 6:7–17

    Google Scholar 

  • Monaco AP, Neve RL, Colletti-Feener C, Bertelson CJ, Kurnit DM, Kunkel LM (1986) Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 323:646–650

    Google Scholar 

  • Monaco AP, Bertelson CJ, Colletti-Feener C, Kunkel LM (1987) Localization and cloning of Xp21 deletion breakpoints involved in muscular dystrophy. Hum Genet 75:221–227

    Google Scholar 

  • Moser H (1984) Review of studies on the proportion and origin of new mutants in Duchenne muscular dystrophy. In: Kate LP ten, Pearson PL, Stadhouders AM (eds) Research into the origin and treatment of muscular dystrophy. Excerpta Medica, Amsterdam, pp 41–52

    Google Scholar 

  • Murphy EA, Cramer DW, Kryscio RJ, Brown CC, Pierce ER (1974) Gonadal mosaicism and genetic counseling for X-linked recessive lethals. Am J Hum Genet 26:207–222

    Google Scholar 

  • Nicholson LV, Johnson MA, Gardner-Medwin D, Bhattacharya S, Harris JB (1990) Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy. Acta Neuropathol (Berl) 80:239–250

    Google Scholar 

  • Ommen GJB van, Bertelson C, Ginjaar HB, Dunnen JT den, Bakker E, Chelly J, Matton M, Essen AJ van, Bartley J, Kunkel LM (1987) Long-range genomic map of the Duchenne muscular dystrophy (DMD) gene: isolation and use of J66 (DXS268), a distal intragenic marker. Genomics 1:329–336

    Google Scholar 

  • Passos-Bueno MR, Lima MABO, Zatz M (1990) Estimate of germinal mosaicism in Duchenne muscular dystrophy. J Med Genet 27:727–728

    Google Scholar 

  • Ried T, Mahler V, Vogt P, Blonden L, Ommen GJB van, Cremer T, Cremer M (1990) Direct carrier detection by in situ suppression hybridization with cosmid clones of the Duchenne/Becker muscular dystrophy locus. Hum Genet 85:581–586

    Google Scholar 

  • Roberts RG, Bentley DR, Barby TF, Manners E, Bobrow M (1990) Direct diagnosis of carriers of Duchenne and Becker muscular dystrophy by amplification of lymphocyte RNA. Lancet 336:1523–1526

    Google Scholar 

  • Roncuzzi L, Ferlini A, Pirozzi A, Romeo G (1986) Origin of new mutations in Duchenne muscular dystrophy. Hum Genet 74:456–460

    Google Scholar 

  • Rosendaal FR, Bröcker-Vriends AH, Houwelingen JC van, Smit C, Varekamp I, Dijck H van, Suurmeijer TP, Vandenbroucke JP, Briet E (1990) Sex ratio of the mutations frequencies in haemophilia A: estimation and meta-analysis. Hum Genet 86:139–146

    Google Scholar 

  • Roses AD (1988) Mutants in Duchenne muscular dystrophy. Implications for prevention. Arch Neurol 45:84–85

    Google Scholar 

  • Wilcox DE, Affara NA, Yates JR, Ferguson-Smith MA, Pearson PL (1985) Multipoint linkage analysis of the short arm of the human X chromosome in families with X-linked dystrophy. Hum Genet 70:365–375

    Google Scholar 

  • Winter RM, Pembrey ME (1982) Does unequal crossing over contribute to the mutation rate in Duchenne muscular dystrophy? Am J Med Genet 12:437–441

    Google Scholar 

  • Wood S, McGillivray BC (1988) Germinal mosaicism in Duchenne muscular dystrophy. Hum Genet 78:282–284

    Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, NL-9713, AW Groningen, The Netherlands

    Anthonie J. van Essen, Hans Scheffer & Leo P. ten Kate

  2. Paediatric Research Unit, The Prince Philip Research Laboratories, Division of Medical and Molecular Genetics, 8th Floor Guy's Tower, Guy's Hospital, SE1 9RT, London, UK

    Stephen Abbs

  3. Unitat de Genètica Molecular, Hospital Santa Creu i Sant Pau, E-08025, Barcelona, Spain

    Montserrat Baiget

  4. Department of Human Genetics, Sylvius Laboratories, Wassenaarseweg 72, NL-2333, AL Leiden, The Netherlands

    Egbert Bakker & Gert-J. B. van Ommen

  5. Laboratoire Central de Biochimie et de Génétique Moléculaire, Hôpital Ambroise Paré, F-92104, Boulogne, Paris, France

    Catherine Boileau

  6. Department of Biochemistry, University of Antwerpen, Universiteitsplein 1, B-2610, Antwerpen, Belgium

    Christine van Broeckhoven

  7. Department of Human Genetics, University of Newcastle upon Tyne, 19 Claremont Place, NE24AA, Newcaste upon Tyne, UK

    Kate Bushby

  8. Institute of Medical Genetics, University Hospital of Wales, CF4 4XN, Heath Park, Cardiff, UK

    Angus Clarke

  9. Institut de Biologie, INSERM U 249 — CRBM/CNRS, Boulevard Henri IV, F-34060, Montpellier, France

    Mireille Claustres

  10. Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Largo G. Gaslini 5, I-16148, Genova, Italy

    Angela E. Covone

  11. Laboratorio Analisi Cliniche, S. Raffaele Hospital, Via Olgettina 60, Milan, Italy

    Maurizio Ferrari

  12. Cattedra di Istologia e Embriologia Generale, Università degli Studi di Modena, Via del Pozzo 71, I-41100, Modena, Italy

    Alessandra Ferlini

  13. UILDM-Rome-section, Instituto di Biologia Cellulare, CNR, Via le Marx 43, I-00137, Rome, Italy

    Giuliana Galluzzi

  14. Institut für Humangenetik der Universität, Koellikerstrasse 2, W-8700, Würzburg, Germany

    Tiemo Grimm

  15. Centrum voor Menselijke Erfelijkheid, Universitaire Ziekenhuizen Leuven, u.z. Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    Caroline Grubben

  16. Service de Biochimie Génétique et Inserm U129, Faculté de Médicine Cochin-Port Royal, F-75014, Paris, France

    Marc Jeanpierre

  17. Department of Medical Genetics, University of Helsinki, Haartmaninkatu 3, SF-00290, Helsinki, Finland

    Helena Kääriäinen

  18. Abteilung Medizinische Genetik, Inselspital, Freiburgstrasse 15, CH-3010, Bern, Switzerland

    Sabina Liechti-Gallati

  19. Instituto di Clinico e Biologica Dell'Eta' Evolutiva, Università Studi Cagliari, Via Jenner s/n, I-09100, Cagliari, Italy

    Marie A. Melis

  20. Laboratoires de Chimie Médicale et de Génétique Médicale, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart Tilman — B35, B-4000, Liège, Belgium

    Jaques E. Poncin

  21. Department of Clinical Genetics, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark

    Marianne Schwartz

  22. Abteilung Molekulare Humangenetik, Zentralinstitut für Molekularbiologie, Robert-Rössel-Strasse 10, O-1115, Berlin-Buch, Germany

    Astrid Speer

  23. Institut für Humangenetik der Freien Universität, Heubnerweg 6, W-1000, 19, Berlin, Germany

    Manfred Stuhrmann

  24. Centre de Génétique Médicale, Université Catholique de Louvain, Avenue E. Mounier 52, B-1200, Brussels, Belgium

    Christine Verellen-Dumoulin

  25. Department of Medical Genetics, Duncan Guthrie Institute of Medical Genetics, University of Glasgow, G3 8SJ, Yorkhill, Glasgow, UK

    Douglas E. Wilcox

Authors
  1. Anthonie J. van Essen
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  2. Stephen Abbs
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  3. Montserrat Baiget
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  4. Egbert Bakker
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  5. Catherine Boileau
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  6. Christine van Broeckhoven
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  7. Kate Bushby
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  8. Angus Clarke
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  9. Mireille Claustres
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  10. Angela E. Covone
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  11. Maurizio Ferrari
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  12. Alessandra Ferlini
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  13. Giuliana Galluzzi
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  14. Tiemo Grimm
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  15. Caroline Grubben
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  16. Marc Jeanpierre
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  17. Helena Kääriäinen
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  18. Sabina Liechti-Gallati
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  19. Marie A. Melis
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  20. Gert-J. B. van Ommen
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  21. Jaques E. Poncin
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  22. Hans Scheffer
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  23. Marianne Schwartz
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  24. Astrid Speer
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  25. Manfred Stuhrmann
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  26. Christine Verellen-Dumoulin
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  27. Douglas E. Wilcox
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  28. Leo P. ten Kate
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van Essen, A.J., Abbs, S., Baiget, M. et al. Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study. Hum Genet 88, 249–257 (1992). https://doi.org/10.1007/BF00197255

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