This article was originally published here
Am J Med Genet A. 2022 January 8. doi: 10.1002 / ajmg.a.62636. Online ahead of print.
WAC-related intellectual disability, also known as DeSanto-Shinawi syndrome, is a rare autosomal dominant genetic disorder caused by pathogenic variants of the WAC gene. This syndrome is characterized by developmental delay, intellectual disability, behavioral abnormalities and dysmorphic facial features, including sunken eyes, a flat nasal bridge, bulbous nasal tip, and synophrys. Chromosomal deletions at 10p12p11 encompassing the WAC gene have been described in patients with a similar phenotype, with developmental delay, intellectual disability, visual impairment, abnormal behavior and dysmorphic features. An important clinical difference between the two groups of patients is that those with large deletions frequently have congenital heart defects, which have rarely been reported in patients with pathogenic variants of WAC. The genes underlying heart defects in patients with the deletion have not yet been fully clarified. Here, we describe two unrelated Portuguese patients with de novo pathogenic variants in the WAC gene, previously unreported in the literature. Both patients present with microcephaly, developmental delay, intellectual disability, behavioral problems and facial dysmorphisms. Interestingly, the youngest patient has a severe congenital heart defect, showing that the intragenic pathogenic variants of WAC may also be associated with heart defects. Therefore, this report expands the phenotypic and genotypic spectrum of this rare syndrome and provides more in-depth information by comparing the clinical characteristics of our patients with previously reported cases.