Expanding the phenotype of PIK3C2A related syndrome: Report of two siblings with novel features and genotype

A pair of siblings was ascertained due to multiple congenital anomalies, including strikingly similar facial, skeletal, and ocular abnormalities. Exome sequencing of both the children and their mother revealed two novel PIK3C2A variants in the siblings, c.4381delC (p.Arg1461Glufs*31) and c.1555C > T (p.Arg519Ter). PIK3C2A belongs to the Class IIa family of Phosphatidylinositol-3-kinases, which create second messenger lipids that regulate a wide range of downstream signaling pathways involved in cell growth, survival and migration. Tiosano et al. (2019) identified the first monogenic disorder associated with biallelic PIK3C2A loss-of-function variants (oculoskeletodental syndrome). The novel syndrome was characterized by short stature, coarse facial features, ocular and skeletal abnormalities. This report describes two additional siblings affected by the PIK3C2A-related syndrome, confirms core clinical features, establishes intrafamilial variability and expands the phenotype to include proteinuria.