De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea

Fan Xia, Matthew N. Bainbridge, Tiong Yang Tan, Michael F. Wangler, Angela E. Scheuerle, Elaine H. Zackai, Margaret H. Harr, V. Reid Sutton, Roopa L. Nalam, Wenmiao Zhu, Margot Nash, Monique M. Ryan, Joy Yaplito-Lee, Jill V. Hunter, Matthew A. Deardorff, Samantha J. Penney, Arthur L. Beaudet, Sharon E. Plon, Eric A. Boerwinkle, James R. LupskiChristine M. Eng, Donna M. Muzny, Yaping Yang, Richard A. Gibbs

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

Original languageEnglish (US)
Pages (from-to)784-789
Number of pages6
JournalAmerican Journal of Human Genetics
Volume94
Issue number5
DOIs
StatePublished - May 1 2014

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Language Development Disorders
Muscle Hypotonia
Sleep Apnea Syndromes
Exome
Mutation
Genetic Association Studies
Nervous System Diseases
Intellectual Disability
Genes
Referral and Consultation
Research

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. / Xia, Fan; Bainbridge, Matthew N.; Tan, Tiong Yang; Wangler, Michael F.; Scheuerle, Angela E.; Zackai, Elaine H.; Harr, Margaret H.; Sutton, V. Reid; Nalam, Roopa L.; Zhu, Wenmiao; Nash, Margot; Ryan, Monique M.; Yaplito-Lee, Joy; Hunter, Jill V.; Deardorff, Matthew A.; Penney, Samantha J.; Beaudet, Arthur L.; Plon, Sharon E.; Boerwinkle, Eric A.; Lupski, James R.; Eng, Christine M.; Muzny, Donna M.; Yang, Yaping; Gibbs, Richard A.

In: American Journal of Human Genetics, Vol. 94, No. 5, 01.05.2014, p. 784-789.

Research output: Contribution to journalArticle

Xia, F, Bainbridge, MN, Tan, TY, Wangler, MF, Scheuerle, AE, Zackai, EH, Harr, MH, Sutton, VR, Nalam, RL, Zhu, W, Nash, M, Ryan, MM, Yaplito-Lee, J, Hunter, JV, Deardorff, MA, Penney, SJ, Beaudet, AL, Plon, SE, Boerwinkle, EA, Lupski, JR, Eng, CM, Muzny, DM, Yang, Y & Gibbs, RA 2014, 'De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea', American Journal of Human Genetics, vol. 94, no. 5, pp. 784-789. https://doi.org/10.1016/j.ajhg.2014.04.006
Xia, Fan ; Bainbridge, Matthew N. ; Tan, Tiong Yang ; Wangler, Michael F. ; Scheuerle, Angela E. ; Zackai, Elaine H. ; Harr, Margaret H. ; Sutton, V. Reid ; Nalam, Roopa L. ; Zhu, Wenmiao ; Nash, Margot ; Ryan, Monique M. ; Yaplito-Lee, Joy ; Hunter, Jill V. ; Deardorff, Matthew A. ; Penney, Samantha J. ; Beaudet, Arthur L. ; Plon, Sharon E. ; Boerwinkle, Eric A. ; Lupski, James R. ; Eng, Christine M. ; Muzny, Donna M. ; Yang, Yaping ; Gibbs, Richard A. / De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 5. pp. 784-789.
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AU - Beaudet, Arthur L.

AU - Plon, Sharon E.

AU - Boerwinkle, Eric A.

AU - Lupski, James R.

AU - Eng, Christine M.

AU - Muzny, Donna M.

AU - Yang, Yaping

AU - Gibbs, Richard A.

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N2 - Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

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