The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype

Area of Science:

• Genetics
• Developmental Biology
• Cellular Biology

Background:

• The Rho family of GTPases, including RHOA, are crucial regulators of fundamental cellular processes such as cell adhesion, migration, and proliferation.
• RHOA plays a key role in stimulating stress fiber formation, focal adhesions, and actomyosin dynamics across various tissues.

Observation:

• Four unrelated individuals presented with a distinct phenotype including hypopigmented skin, dental anomalies, body asymmetry, and limb length discrepancies (hemihypotrophy).
• Brain MRI anomalies were also noted in affected individuals, suggesting a broader impact on development.

Findings:

• Whole-exome and ultra-deep amplicon sequencing identified a recurrent, identical RHOA missense variant (c.139G>A; p.Glu47Lys) in a postzygotic state in all affected individuals.
• Molecular modeling predicted that the p.Glu47Lys substitution specifically disrupts RHOA's interaction with PKN-type binding domain effectors, impairing downstream signaling.

Implications:

• The findings establish the recurrent postzygotic RHOA missense variant p.Glu47Lys as the causative agent of a specific human mosaic disorder.
• This discovery advances our understanding of RHOA's role in human development and the genetic basis of mosaic conditions.
• Further research into RHOA signaling pathways may reveal therapeutic targets for related developmental disorders.