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Am J Hum Genet. 2014 May 1;94(5):784-9. doi: 10.1016/j.ajhg.2014.04.006.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Pediatrics, University of Melbourne, Parkville VIC 3052, Australia.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
5
Tesserae Genetics, Dallas, TX 75230, USA.
6
The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
8
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
9
Texas Children's Hospital, Houston, TX 77030, USA.
10
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
11
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: agibbs@bcm.edu.

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.

PMID:
24791903
PMCID:
PMC4067559
DOI:
10.1016/j.ajhg.2014.04.006
[Indexed for MEDLINE]
Free PMC Article
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