Patients with DeSanto–Shinawi syndrome: Further extension of phenotype from Italy

Abstract

Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these—c.167delA, p.(Asn56I1efs*136) and c.1746G>C, p.(Gln582His)—are novel pathogenic variants, and the third—c.1837C>T, p(Arg613*)—has been previously described. Diseases associated with WAC include DeSanto–Shinawi syndrome; to date, de novo heterozygous constitutional pathogenic WAC variants have caused a syndromic form of intellectual disability and mild dysmorphic features in 33 patients, yet potential associations with other clinical manifestations, such as oligomenorrhea and hyperandrogenism, remain unknown, because the phenotypic spectrum of the condition has not yet been delineated. The patient bearing the novel c.167delA WAC gene variant presented a normal psychomotor development, oligomenorrhea, hyperandrogenism, and hirsutism, and hirsutism was also observed in the patient with the c.1746G>C WAC gene variant. Hypertrichosis and hirsutism have been described in nine DeSanto–Shinawi patients, only in 17 of the 33 aforementioned patients thus far reported this aspect, and no hormonal-pattern data are available. In conclusion, we note that the pathogenic c.167delA WAC variant may be associated with a mild phenotype; and in addition to the neurodevelopmental problems nearly all DeSanto–Shinawi patients experience (i.e., intellectual disability and/or developmental delay), we recommend the addition of mild dysmorphic features, hirsutism, and hypertrichosis to this clinical presentation.