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Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing

Abstract

Several X-linked disorders affect females disproportionately or exclusively. These including focal dermal hypoplasia1,2, oral-facial-digital syndrome type I (ref. 3) and epilepsy with bilateral periventricular heterotopias4. X-linked dominant inheritance with male lethality is probably responsible for sex-limited expression of these disorders, as affected women have frequent spontaneous abortions and the sex ratio of their live offspring is often skewed5. The same inheritance pattern has been proposed for Rett syndrome6, Aicardi syndrome7 and microphthalmia with linear skin defects8, but in these sporadic conditions, evidence of male lethality is lacking. We investigated an unusual family with epilepsy and mental retardation limited to females (EFMR, ♯121250 in ref. 9); this disorder is transmitted both by females and by completely unaffected carrier males. Assignment of the EFMR disease locus (EFMR) to the X chromosome indicates that selective involvement of females in X-linked disease may in some instances result from male sparing rather than male lethality.

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References

  1. Goltz, R.W., Peterson, W.C., Gorlin, R.J. & Ravits, H.G. Focal dermal hypoplasia. Arch. Dermatol. 86, 708–717 (1962).

    Article  CAS  PubMed  Google Scholar 

  2. Temple, I.K., MacDowall, P., Baraitser, M. & Atherton, D.J. Focal dermal hypoplasia (Goltz syndrome). J. Med. Genet. 27, 180–187 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Melnick, M. & Shields, E.D. Orofaciodigital syndrome, type I: a phenotypic and genetic analysis. Oral Surg. Oral Med. Oral Pathol. 40, 599–610 (1975).

    Article  CAS  PubMed  Google Scholar 

  4. Eksioglu, Y.Z. et al. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 7, 117–119 (1992).

    Google Scholar 

  5. Wettke-Schafer, R. & Kantner, G. X-linked dominant inherited diseases with lethality in hemizygous males. Hum. Genet. 64, 1–23 (1983).

    Article  CAS  PubMed  Google Scholar 

  6. Hagberg, B., Aicardi, J., Dias, K. & Ramos, O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome; report of 35 cases. Ann. Neurol. 14, 471–479 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. Donnenfeld, A.E. et al. Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome. Am. J. Med. Genet. 32, 461–467 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Lindsay, E.A. et al. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization. Am. J. Med. Genet. 49, 229–234 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. McKusick, V.A., Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders (Johns Hopkins University Press, Baltimore, 1994).

    Google Scholar 

  10. Juberg, R.C. & Hellman, C.D. A new familial form of convulsive disorder and mental retardation limited to females. J. Pediatr. 79, 726–732 (1971).

    Article  CAS  PubMed  Google Scholar 

  11. Fabisiak, K. & Erickson, R.P. A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms. Clin. Genet. 38, 353–358 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Hudson, T.J. et al. An STS-based map of the human genome. Science 270, 1945–1954 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Murray, J.C. et al. and the Cooperative Human Linkage Center (CHLC). A comprehensive human linkage map with centimorgan density. Science 265, 2049–2054 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Brown, C.J. et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Penny, G.D., Kay, G.F., Sheardown, S.A., Rastan, S. & Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Allen, R.C., Zoghbi, H.Y., Moseley, A.B., Rosenblatt, H.M. & Belmont, J.W. Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51, 1229–1239 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kapusta, L., Brunner, H.G. & Hamel, B.C. Craniofrontonasal dysplasia. Eur. J. Pediatr. 151, 837–841 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Vaillaud, J.C., Martin, J., Szepetowski, G. & Robert, J.M. Le syndrome oro-facio-digital: étude clinique et génétique à propos de 10 cas observés dans une même famille. Rev. Pediatr. 4, 383–392 (1968).

    Google Scholar 

  21. Page, D.C., Harper, M.E., Love, J. & Botstein, D. Occurrence of a transposition from the X-chromosome long arm to the Y-chromosome short arm during human evolution. Nature 311, 119–123 (1984).

    Article  CAS  PubMed  Google Scholar 

  22. Mumm, S., Molini, B., Terrell, J., Srivastava, A. & Schlessinger, D. Evolutionary features of the 4 Mb Xq21. 3 XV homology region revealed by a map at 60 kb resolution. Genome Res. (in the press).

  23. Johnson, W.F. Metabolic interference and the +/− heterpzygote: a hypothetical form of simple inheritance which is neither dominant nor recessive. Am. J. Hum. Genet. 32, 374–386 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Miller, A.P. et al. Three genes that escape X chromosome inactivation are clustered within a 6 Mb YAC contig and STS map in Xp11.21–p11.22. Hum. Mot. Genet. 4, 731–739 (1995).

    Article  CAS  Google Scholar 

  25. Jani, M.M., Torchia, B.S., Pai, G.S. & Migeon, B.R. Molecular characterization of tiny ring X chromosomes from females with functional X chromosome disomy and lack of Cis X inactivation. Genomics 27, 182–188 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Ryan, S.G. et al. Startle disease, or hyperexplexia: response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis. Ann. Neurol. 31, 663–668 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Weber, J.L. & May, P.E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. Hum. Genet. 44, 388–396 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Harlow, E. & Lane, D. Antibodies: A Laboratory Manual (Cold Spring Harbor, Cold Spring Harbor, NY, 1988).

    Google Scholar 

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Correspondence to Stephen G. Ryan.

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Ryan, S., Chance, P., Zou, CH. et al. Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nat Genet 17, 92–95 (1997). https://doi.org/10.1038/ng0997-92

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