DeSanto-Shinawi syndrome is molecularly defined by the presence of pathogenic loss-of-function mutations in WAC gene on chromosome 10, consistent with an autosomal dominant inheritance pattern. All individuals reported to date present the disorder as a result of a de novo mutation in WAC.
Individuals with deletions of WAC may present with similar phenotypes although the phenotypic spectrum and severity, including the degree of developmental delay as well as the presence of congenital malformations, may be confounded by the concurrent deletion of other genes.
Molecular confirmation is necessary for a definitive diagnosis. Most of the affected individuals have been diagnosed through whole exome sequencing, perhaps due to the relatively unspecific facial and general clinical findings. Targeted Sanger sequencing can also be used for the detection of pathogenic variants when the phenotype is suggestive, as well as the presence of a variant that has previously been identified in other affected family members.
Of note, recurrence in the same family of unaffected parents has been reported, strongly suggesting the possibility of germline mosaicism in one of the parents. Prenatal testing may be considered for pregnancies at increased risk, in families in which the pathogenic variant has been identified.