WASHC4 – Autosomal Recessive Non-Syndromic Intellectual Disability

WASHC4 (HGNC:29174) has been implicated in autosomal recessive non-syndromic intellectual disability (MONDO:0019502). The gene was first linked to this phenotype in 2011 in a large consanguineous family with seven affected individuals displaying moderate intellectual disability and short stature (PMID:21498477). In 2020, exome sequencing of two unrelated families identified three additional patients with compound heterozygous WASHC4 variants presenting syndromic intellectual disability with macrocephaly, skeletal anomalies, dysmorphic features and sensorineural hearing loss (PMID:31953988).

Genetic evidence supports an autosomal recessive inheritance pattern with a total of ten probands from three unrelated families. Variants include truncating alleles (e.g., c.1786C>T (p.Arg596Ter)) and multiple missense changes (p.Asp1048Gly, p.Lys1079Arg, p.His503Arg) segregating with disease in the consanguineous pedigree and in compound heterozygosity in non-consanguineous cases. Segregation analysis confirmed co-segregation of homozygous and compound heterozygous variants with the phenotype in affected relatives. No pathogenic variant carriers were phenotypically affected, consistent with recessive transmission.

Functional studies indicate that WASHC4 loss-of-function destabilizes the WASH complex, impairing Arp2/3-dependent actin polymerization and endosomal tubule fission. In patient fibroblasts and zebrafish knockdown models, WASHC4 deficiency leads to disrupted protein clearance, endo-lysosomal dysfunction and neuromuscular defects, aligning with skeletal and cognitive features of the human phenotype (PMID:34599609).

A mouse knock-in model carrying the human WASHC4 c.3056C>G (p.Pro1019Arg) variant exhibits reduced WASHC4 protein levels, perturbations of endosomal and lysosomal pathways, neurodegeneration and progressive motor deficits. Retrospective patient data also revealed movement abnormalities mirroring the murine phenotype, reinforcing a causative role for WASHC4 dysfunction in cognitive and motor impairments (PMID:33749590).

Integrating genetic and experimental data yields a Strong clinical validity classification. The genetic evidence demonstrates robust segregation, multi-family replication and a clear variant spectrum, while functional assays provide concordant mechanistic insights. This gene-disease association informs diagnostic sequencing panels for intellectual disability and suggests endo-lysosomal pathways as potential therapeutic targets.

Key Take-home: Biallelic WASHC4 variants cause autosomal recessive non-syndromic intellectual disability through loss-of-function, with consistent genetic segregation and experimental validation enabling clinical diagnosis and guiding future research.

References

• Human molecular genetics • 2011 • Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP. PMID:21498477
• American journal of medical genetics. Part A • 2020 • Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature. PMID:31953988
• eLife • 2021 • Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans. PMID:33749590
• The Journal of pathology • 2022 • Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement. PMID:34599609

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