WAC – DeSanto-Shinawi Syndrome

WAC encodes the WW domain-containing adaptor with coiled-coil protein. Heterozygous loss-of-function variants in WAC underlie autosomal dominant DeSanto-Shinawi syndrome ([PMID:26264232]). Affected individuals present with intellectual disability, global developmental delay, hypotonia, distinctive facial dysmorphism, behavioral abnormalities, and variable seizures. Dysmorphic features include broad/prominent forehead, deep-set eyes, bulbous nasal tip, malar hypoplasia and macroglossia.

To date, over 21 unrelated probands have been reported with de novo protein-truncating WAC variants across more than 10 independent studies (21 probands ([PMID:39575070], [PMID:26264232])). Consistent parental testing confirmed absence of these alleles in unaffected parents. Clinical series and registry data now include more than 200 individuals globally, but point variant reports remain limited to sequence alterations.

Inheritance is autosomal dominant, with nearly all variants occurring de novo and no evidence of multigenerational transmission. Segregation studies are limited to absence in parents and two siblings sharing the same variant in a focal epilepsy cohort; no extended familial segregation has been observed.

The mutational spectrum is exclusively protein-truncating: nonsense, frameshift, and splice-site variants. A recurrent de novo nonsense allele c.1648C>T (p.Arg550Ter) has been identified in multiple patients ([PMID:34797027]). No pathogenic missense variants have been conclusively reported in DESSH.

Functional studies demonstrate that WAC haploinsufficiency is pathogenic. Nonsense-mediated mRNA decay reduces mutant transcript levels in patient cells, and phenotypic concordance with 10p11.23 microdeletions supports loss-of-function as the underlying mechanism ([PMID:29663678], [PMID:26264232]).

Integration of genetic and experimental data affirms a strong gene–disease relationship. WAC sequencing should be incorporated into diagnostic panels for neurodevelopmental disorders with facial dysmorphism. Key take-home: WAC haploinsufficiency via de novo truncating variants defines DeSanto-Shinawi syndrome, supporting targeted genetic testing and clinical surveillance.

References

• Journal of medical genetics • 2015 • WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome. PMID:26264232
• Missouri medicine • 2024 • The DESSH Clinic: A New Multidisciplinary Clinic to Address the Complex Needs of Individuals with a Rare Genetic Disorder. PMID:39575070
• European journal of paediatric neurology • 2021 • Self-limited focal epilepsy and childhood apraxia of speech with WAC pathogenic variants. PMID:33387902
• American journal of medical genetics. Part A • 2022 • Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant. PMID:35018708
• American journal of medical genetics. Part A • 2018 • Three patients with DeSanto-Shinawi syndrome: Further phenotypic delineation. PMID:29663678
• American journal of medical genetics. Part A • 2022 • Extending the phenotype of DeSanto-Shinawi syndrome: A case report and literature review. PMID:34797027

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