title: Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia, ataxia, and intellectual disability.
abstract: DOCK3 encodes the dedicator of cytokinesis 3 protein, a member of the DOCK180 family of proteins that are characterized by guanine-nucleotide exchange factor activity. DOCK3 is expressed exclusively in the central nervous system and plays an important role in axonal outgrowth and cytoskeleton reorganization. Dock3 knockout mice exhibit motor deficiencies with abnormal ataxic gait and impaired learning. We report 2 siblings with biallelic loss-of-function variants in DOCK3. Diagnostic whole-exome sequencing (WES) and chromosomal microarray were performed on a proband with severe developmental disability, hypotonia, and ataxic gait. Testing was also performed on the proband's similarly affected brother. A paternally inherited 458 kb deletion in chromosomal region 3p21.2 disrupting the DOCK3 gene was identified in both affected siblings. WES identified a nonsense variant c.382C>G (p.Gln128*) in the DOCK3 gene (NM_004947) on the maternal allele in both siblings. Common features in both affected individuals include severe developmental disability, ataxic gait, and severe hypotonia, which recapitulates the Dock3 knockout mouse phenotype. We show that complete DOCK3 deficiency in humans leads to developmental disability with significant hypotonia and gait ataxia, probably due to abnormal axonal development.
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California.
authors.forename: K L
authors.identifier: http://orcid.org/0000-0001-8249-0549
authors.initials: KL
authors.lastname: Helbig
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California.
authors.forename: C
authors.initials: C
authors.lastname: Mroske
authors.affiliation: The George A. Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York.
authors.forename: D
authors.initials: D
authors.lastname: Moorthy
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California.
authors.forename: S A
authors.initials: SA
authors.lastname: Sajan
authors.affiliation: The George A. Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: M
authors.initials: M
authors.lastname: Velinov
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009123:Muscle Hypotonia / Q000235:genetics* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D035781:Siblings
chemical_list: D002352:Carrier Proteins; C485840:DOCK3 protein, human; C410623:Dock3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins
keywords: DOCK3; ataxia; developmental disability; whole-exome sequencing