title: De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.
abstract: Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Ganka
authors.initials: G
authors.lastname: Douglas
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Peyton Manning Children's Hospital at St. Vincent, Indianapolis, Indiana 46260, USA;
authors.forename: Luis F
authors.initials: LF
authors.lastname: Escobar
authors.affiliation: Peyton Manning Children's Hospital at St. Vincent, Indianapolis, Indiana 46260, USA;
authors.forename: Megan E
authors.initials: ME
authors.lastname: Tucker
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Joan
authors.initials: J
authors.lastname: Stoler
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Lance H
authors.initials: LH
authors.lastname: Rodan
authors.affiliation: Stein Life Child Neurology, Irvine, California 92604, USA;
authors.forename: Diane
authors.initials: D
authors.lastname: Stein
authors.affiliation: Cook Children's Medical Center, Fort Worth, Texas 76104, USA;
authors.forename: Warren
authors.initials: W
authors.lastname: Marks
authors.affiliation: Division of Medical Genetics, Lucile Packard Children's Hospital Stanford, Palo Alto, California 94304, USA;
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.affiliation: Division of Medical Genetics, Lucile Packard Children's Hospital Stanford, Palo Alto, California 94304, USA;
authors.forename: Julia
authors.initials: J
authors.lastname: Platt
authors.affiliation: Division of Medical Genetics, Lucile Packard Children's Hospital Stanford, Palo Alto, California 94304, USA;
authors.forename: Rachel
authors.initials: R
authors.lastname: Cox
authors.affiliation: Nemours Children's Hospital, Orlando, Florida 32827, USA;
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Wheeler
authors.affiliation: Nemours Children's Hospital, Orlando, Florida 32827, USA;
authors.forename: Carrie
authors.initials: C
authors.lastname: Crain
authors.affiliation: University of Minnesota Medical Center, Minneapolis, Minnesota 55454, USA;
authors.forename: Amy
authors.initials: A
authors.lastname: Calhoun
authors.affiliation: University of Minnesota Medical Center, Minneapolis, Minnesota 55454, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tryon
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877, USA;
authors.forename: Patrik
authors.initials: P
authors.lastname: Vitazka
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
keywords: central hypotonia; intellectual disability, severe; severe global developmental delay