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Case Reports
. 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

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Free PMC article
Case Reports

De Novo Truncating Mutations in AHDC1 in Individuals With Syndromic Expressive Language Delay, Hypotonia, and Sleep Apnea

Fan Xia et al. Am J Hum Genet. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Pedigrees and Mutations of Four Affected Families
Figure 2
Figure 2
Facial Features of Probands (A) Subject 1 (17 months old) with a round face, full cheeks, horizontal eyebrows, a depressed nasal bridge, anteverted nares, hypoplastic alae nasi, tented upper-lip vermillion, and microstomia. (B) Subject 2 (4 years old) with thin eyebrows, a depressed nasal bridge, a bulbous nasal tip, and protuberant ears. (C) Subject 3 (8 years old) with horizontal eyebrows, low-set ears, simple earlobes, and micrognathia. (D) Subject 4 (21 months old) with a round face, full cheeks, horizontal eyebrows, a depressed nasal bridge, anteverted nares, tented upper-lip vermillion, and microstomia. (E and F) Front (E) and side (F) views of subject 4 (9 years old) with a round face, full cheeks, horizontal eyebrows, an acute nasal angle, and fleshy pinna.
Figure 3
Figure 3
AHDC1 Genomic Organization (A) Chromosomal location of AHDC1 and the genomic region surrounding it. (B and C) Organization of AHDC1 (B) and the AT-hook DNA-binding region, conserved regions, and location of the three different truncating alterations in the disorder (C). The histogram shows evolutionary conservation (see Figure S3 for details).

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