WASHC5 – Ritscher-Schinzel syndrome

WASHC5 encodes strumpellin, a core subunit of the WASH complex involved in endosomal actin nucleation. Biallelic pathogenic variants in WASHC5 cause Ritscher-Schinzel syndrome type 1 (RTSCS1), an autosomal recessive disorder marked by distinctive craniofacial features, cerebellar and cardiovascular malformations, and neurodevelopmental impairment.

Autosomal recessive inheritance of WASHC5-related RTSCS1 is supported by eight unrelated individuals homozygous for a splice-site or loss-of-function variant identified by homozygosity mapping (PMID:24065355) and four affected siblings with compound heterozygous loss-of-function variants in two unrelated families (PMID:36130690). Segregation was confirmed by parental carrier status and prenatal ultrasound findings in multiple fetuses.

The variant spectrum in RTSCS1 includes nonsense, frameshift, and splice-site mutations leading to loss of strumpellin function. A representative allele is c.3163C>T (p.Gln1055Ter), converting a glutamine to a premature termination codon and truncating the protein within the SHRC domain (PMID:24065355).

Segregation analysis across families demonstrated co-segregation of WASHC5 variants with disease in affected siblings and consanguineous pedigrees, with three additional affected relatives beyond the index cases in the compound heterozygous family (PMID:36130690).

Functional studies in patient‐derived cells showed an ~8-fold reduction of the exon-skipped transcript and a ~60 % decrease in strumpellin protein, consistent with a loss-of-function mechanism driving RTSCS1 (PMID:24065355).

Phenotypic features in WASHC5-deficient individuals include macrocephaly (HP:0000256), global developmental delay (HP:0001263), intellectual disability (HP:0001249), facial dysmorphism (HP:0000271), gait ataxia (HP:0002066), and variable cardiac anomalies such as abnormal heart morphology (HP:0001627). Prenatal findings can include increased nuchal translucency.

Collectively, twelve independent affected individuals across two cohorts provide strong genetic and moderate functional evidence for WASHC5 in RTSCS1. Clinical testing for biallelic WASHC5 variants enables definitive diagnosis, informs management of multisystem involvement, and guides reproductive counseling.

References

• Unspecified Journal • Unspecified Year • Strumpellin splice-site mutation in Ritscher-Schinzel syndrome PMID:24065355
• European Journal of Medical Genetics • 2022 • Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 related Ritscher-Schinzel syndromes PMID:36130690

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