Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females

Elena Pegoraro, R. Neil Schimke, Kiichi Arahata, Yukiko Hayashi, Harvey Stern, Harold Marks, Mark R. Glasberg, James Edwin Carroll, Joseph W. Taber, Henry B. Wessel, Steven C. Bauserman, Warren A. Marks, Helga V. Toriello, James V. Higgins, Staci Appleton, Lisa Schwartz, Carlos A. Garcia, Eric P. Hoffman

Research output: Contribution to journalArticle

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Abstract

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients-10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

Original languageEnglish (US)
Pages (from-to)989-1003
Number of pages15
JournalAmerican Journal of Human Genetics
Volume54
Issue number6
StatePublished - Jun 8 1994

Fingerprint

Dystrophin
X Chromosome Inactivation
Mutation
Genes
X-Linked Genes
Bayes Theorem
Duchenne Muscular Dystrophy
Monozygotic Twins
Molecular Pathology
Germ-Line Mutation
Genetic Counseling
Muscular Diseases
Mutation Rate
Prenatal Diagnosis
Routine Diagnostic Tests
Biopsy
Muscles
DNA
Incidence

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Pegoraro, E., Neil Schimke, R., Arahata, K., Hayashi, Y., Stern, H., Marks, H., ... Hoffman, E. P. (1994). Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. American Journal of Human Genetics, 54(6), 989-1003.

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. / Pegoraro, Elena; Neil Schimke, R.; Arahata, Kiichi; Hayashi, Yukiko; Stern, Harvey; Marks, Harold; Glasberg, Mark R.; Carroll, James Edwin; Taber, Joseph W.; Wessel, Henry B.; Bauserman, Steven C.; Marks, Warren A.; Toriello, Helga V.; Higgins, James V.; Appleton, Staci; Schwartz, Lisa; Garcia, Carlos A.; Hoffman, Eric P.

In: American Journal of Human Genetics, Vol. 54, No. 6, 08.06.1994, p. 989-1003.

Research output: Contribution to journalArticle

Pegoraro, E, Neil Schimke, R, Arahata, K, Hayashi, Y, Stern, H, Marks, H, Glasberg, MR, Carroll, JE, Taber, JW, Wessel, HB, Bauserman, SC, Marks, WA, Toriello, HV, Higgins, JV, Appleton, S, Schwartz, L, Garcia, CA & Hoffman, EP 1994, 'Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females', American Journal of Human Genetics, vol. 54, no. 6, pp. 989-1003.
Pegoraro E, Neil Schimke R, Arahata K, Hayashi Y, Stern H, Marks H et al. Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. American Journal of Human Genetics. 1994 Jun 8;54(6):989-1003.
Pegoraro, Elena ; Neil Schimke, R. ; Arahata, Kiichi ; Hayashi, Yukiko ; Stern, Harvey ; Marks, Harold ; Glasberg, Mark R. ; Carroll, James Edwin ; Taber, Joseph W. ; Wessel, Henry B. ; Bauserman, Steven C. ; Marks, Warren A. ; Toriello, Helga V. ; Higgins, James V. ; Appleton, Staci ; Schwartz, Lisa ; Garcia, Carlos A. ; Hoffman, Eric P. / Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. In: American Journal of Human Genetics. 1994 ; Vol. 54, No. 6. pp. 989-1003.
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AU - Marks, Warren A.

AU - Toriello, Helga V.

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AU - Schwartz, Lisa

AU - Garcia, Carlos A.

AU - Hoffman, Eric P.

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N2 - Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients-10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

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