DOCKopathies: A systematic review of the clinical pathologies associated with human DOCK pathogenic variants

Abstract

The Dedicator of Cytokinesis (DOCK) family (DOCK1-11) of genes are essential mediators of cellular migration, growth, and fusion in a variety of cell types and tissues. Recent advances in whole-genome sequencing of patients with undiagnosed genetic disorders have identified several rare pathogenic variants in DOCK genes. We conducted a systematic review and performed a patient database and literature search of reported DOCK pathogenic variants that have been identified in association with clinical pathologies such as global developmental delay, immune cell dysfunction, muscle hypotonia, and muscle ataxia among other categories. We then categorized these pathogenic DOCK variants and their associated clinical phenotypes under several unique categories: developmental, cardiovascular, metabolic, cognitive, or neuromuscular. Our systematic review of DOCK variants aims to identify and analyze potential DOCK-regulated networks associated with neuromuscular diseases and other disease pathologies, which may identify novel therapeutic strategies and targets. This systematic analysis and categorization of human-associated pathologies with DOCK pathogenic variants is the first report to the best of our knowledge for a unique class in this understudied gene family that has important implications in furthering personalized genomic medicine, clinical diagnoses, and improve targeted therapeutic outcomes across many clinical pathologies.

Keywords: DOCK; hypotonia; intellectual disability; skeletal muscle.

Figure 1:. Summary of Methodology.

Meta-analysis was conducted using two databases, PubMed and ClinVar. Initial inquiry began with PubMed (A) in which we reviewed 1000 available primary articles on DOCK variants. We continued our search analyzing reported variants in ClinVar (B) in which we sorted each variant as reported by ClinVar in their respective categories.

Figure 2:. All DOCK variants identified and sorted in ClinVar.

Comprehensive analysis at all DOCK variants identified on ClinVar. We sorted variants for their percentage (%) pathogenicity (A), by molecular consequence as either frameshift, nonsense, or missense (B) and sorted by variant type, as either deletion, duplication, indel, insertion, or single nucleotide (C).

Figure 3:. DOCK variant molecular consequences.

Each pathogenic DOCK variant for each subclass (1–11) were analyzed by molecular consequence as reported by ClinVar.

Figure 4:. DOCK Mutation Type.

Each pathogenic DOCK variant for each subclass (1–11) was analyzed by variant type, either duplication, deletion, indel, insertion etc. as reported by ClinVar.

Figure 5:. Clinical Symptoms of DOCK pathogenic variants.

DOCK pathogenic variants were identified on ClinVar and were collectively categorized by several classifications: ‘Developmental’, ‘Cardiovascular’, ‘Cognitive’, ‘Metabolic’, ‘Nervous system’, and if there were multiple conditions associated with each category they were sorted as ‘2 or more’.