title: De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Pediatrics, University of Melbourne, Parkville VIC 3052, Australia.
authors.forename: Tiong Yang
authors.initials: TY
authors.lastname: Tan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
authors.affiliation: Tesserae Genetics, Dallas, TX 75230, USA.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Scheuerle
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Harr
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Roopa L
authors.initials: RL
authors.lastname: Nalam
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wenmiao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Margot
authors.initials: M
authors.lastname: Nash
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Yaplito-Lee
authors.affiliation: Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Penney
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: 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.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics*; D009154:Mutation; D012891:Sleep Apnea Syndromes / Q000235:genetics*; D013577:Syndrome
chemical_list: C000589131:AHDC1 protein, human; D004268:DNA-Binding Proteins