RAP1B is a RAS-superfamily small GTP-binding protein involved in numerous cell processes. Pathogenic gain-of-function variants in this gene have been associated with RAP1B-related syndromic thrombocytopenia, an ultrarare disorder characterized by hematologic abnormalities, neurodevelopmental delays, growth delay, and congenital birth defects including cardiovascular, genitourinary, neurologic, and skeletal systems. We report a 23-year-old male with a novel, de novo RAP1B gain-of-function variant identified on genome sequencing. This is the third reported case which expands the molecular and phenotypic spectrum of RAP1B-related syndromic thrombocytopenia.

Hardikar syndrome (HS) is a MED12‐related ultra‐rare multiple congenital malformation syndrome known to affect the gastrointestinal, cardiac, and genitourinary systems among other features including cleft lip/palate and pigmentary retinopathy. Only 10 patients affected with HS have been previously described in literature, of which seven were molecularly confirmed. We report a 20‐year‐old and a 13‐month‐old patient with HS diagnosed by exome sequencing bringing the total number of clinically diagnosed cases to 12 and MED12 associated to 9. We describe previously unreported molecular and clinical findings associated with HS and review all reported cases to permit prompt diagnosis, appropriate management, and genetic counseling of HS patients.