RHOA-associated disorder can be non-mosaic

Recurrent somatic mosaic pathogenic variants of RHOA have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic [EDFAOB]. All 12 previously reported patients had somatic mosaicism for RHOA variants. Conversely, no patients with non-mosaic germline variants of RHOA have been reported. The absence of non-mosaic patients has been explained by the presumed lethal effect of all RHOA variants in non-mosaic status. Here we report an 11-month-old female with EDFAOB-like features but without Blaschko's skin lesions or asymmetry. Characteristic features included hypertelorism, 2–3 toes cutaneous syndactyly, cleft palate and duplicated uterus and kidney malformations. She carried the non-mosaic de novo germline variant RHOA:c.202C>A,p.(Arg68Ser) near the hotspot in the switch II region in peripheral blood and buccal swabs. The documentation of a living patient with a non-mosaic germline variant of RHOA negates the previous notion that patients with RHOA variants are not viable. The differential diagnosis of a “non-mosaic” RHOA-related disorder would include Ectodermal Dysplasia-Ectrodactyly-Clefting syndrome, as both conditions share ectodermal dysplasia, finger anomalies, and clefting. This phenotypic similarity may be explained by the known molecular interaction between TP63, the gene responsible for EEC syndrome, and RHOA. RHOA is a member of the RAC subfamily of small Rho family guanosine triphosphatases, which include RHOA, RAC1, RAC3, and CDC42 (Takenouchi-Kosaki syndrome). The documentation of germline RHOA-associated intellectual disability in the present article establishes that variants in all three genes of the RAC subfamily of small Rho family GTPases are associated with neurodevelopmental disorders.