DOCK6 – DOCK6-Related Adams-Oliver Syndrome

DOCK6 loss-of-function variants underlie an autosomal-recessive form of Adams-Oliver syndrome (AOS), a rare disorder combining scalp aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). While dominant forms of AOS exist, DOCK6 mutations have been identified in multiple unrelated AR cases, establishing a consistent genotype–phenotype correlation.

Genetic Evidence

Autosomal-recessive inheritance is supported by homozygous and compound heterozygous truncating DOCK6 variants segregating with disease in at least 8 families. Homozygous truncating mutations were first described in two unrelated probands with ACC and TTLD ([PMID:21820096]). Subsequent case series and cohort studies reported truncating or splice-site variants in over 20 unrelated individuals (PMID:25824905, PMID:29924900), reaching the ClinGen genetic evidence cap.

Segregation and Variant Spectrum

Segregation of DOCK6 variants in multiple sibships affirms pathogenicity. Documented variants include frameshift and nonsense changes, e.g., c.616_617del (p.Leu206fs), as well as essential splice-site disruptions. Recurrent loss-of-function alleles have been observed across diverse populations, with no apparent founder effect.

Functional Evidence

DOCK6 encodes a guanine nucleotide exchange factor for Cdc42 and Rac1, critical for actin cytoskeleton dynamics. Patient fibroblasts exhibited defective actin organization consistent with diminished DOCK6 activity ([PMID:21820096]). Minigene assays confirmed aberrant splicing for intronic variants (c.4106+2T>C) leading to premature termination ([PMID:30898718]).

Integration and Conclusion

Collectively, >20 AR probands with biallelic DOCK6 loss-of-function variants, autosomal-recessive segregation in multiple families, and concordant functional studies provide definitive evidence for DOCK6 in AOS pathogenesis. These findings support incorporation of DOCK6 screening in diagnostic panels for AOS and related neurovascular anomalies.

Key Take-home: DOCK6 truncating variants cause autosomal-recessive AOS via impaired actin cytoskeleton regulation, informing molecular diagnosis and genetic counseling.

References

• American journal of human genetics • 2011 • Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. PMID:21820096
• Human Mutation • 2015 • DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies. PMID:25824905
• Human Mutation • 2018 • Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort. PMID:29924900
• Gene • 2019 • Novel compound heterozygous mutations of the DOCK6 gene in a familial case of Adams-Oliver syndrome 2. PMID:30898718

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