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Research‐Based Whole Genome Sequencing Identifies Biallelic Loss of Function Variants in DOCK3 Gene Causing DOCK3 ‐Related Disorder: The End of a Diagnostic Journey for This Family
Author(s) -
Liaqat Khurram,
Treat Kayla,
Mantcheva Lili,
McLaughlin Aaron,
Breman Amy,
McPheron Molly,
Conboy Erin,
Vetrini Francesco
Publication year - 2025
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.14741
Subject(s) - hypotonia , exome sequencing , genetics , biology , intellectual disability , neurodevelopmental disorder , disease gene identification , ataxia , gene , mutation , neuroscience
ABSTRACT The DOCK3 gene (NM_004947.5) is located on chromosome 3p21.2 spanning 53 exons and encodes the dedicator of cytokinesis 3 protein. DOCK3 belongs to the family of guanine nucleotide exchange factors (GEFs) that activate GTPases. DOCK3 is expressed almost exclusively in the central nervous system and has been shown to promote axonal outgrowth. Biallelic disruptions of DOCK3 are implicated in a neurodevelopmental disorder presenting with intellectual disability, hypotonia and ataxia (OMIM: 618292). We report a 9‐year‐old female with global developmental delay, moderate intellectual disability, wide‐based and ataxic gait, hypotonia, benign nocturnal myoclonus, bifid uvula, moderate obstructive sleep apnea, and alternating esotropia. Prior to enrollment in the Undiagnosed Rare Disease Clinic (URDC), the patient's clinical exome testing was negative. The subsequent enrollment in URDC allowed further research investigations through whole genome sequencing (GS) that identified two compound heterozygous variants in the DOCK3 gene, ultimately yielding an unequivocal definitive molecular diagnosis.