RHOA – Ectodermal Dysplasia With Facial Dysmorphism and Acral, Ocular, and Brain Anomalies

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (MONDO:0032884) is a rare neuroectodermal syndrome presenting with linear skin hypopigmentation along Blaschko’s lines, facial and limb asymmetry, dental anomalies, digital malformations, and white matter hyperintensities on MRI with preserved intellectual function. Two unrelated pediatric patients exhibited postzygotic somatic mosaicism for a recurrent RHOA mutation, c.139G>A (p.Glu47Lys), detected at allele fractions of 20% and 10% in hypopigmented skin but absent in blood leukocytes and parental DNA, supporting a pathogenic role via tissue‐restricted mosaic distribution (2 probands (PMID:39564940)).

The c.139G>A (p.Glu47Lys) substitution affects the switch I region of RhoA, a critical locus for GTPase‐activating protein (GAP) interaction and GTP hydrolysis. Structural and biochemical studies of RhoA–p190GD complexes demonstrate that disruption of key switch I residues abrogates GAP‐stimulated GTP hydrolysis and effector binding, indicating that the Glu47Lys change likely perturbs RhoA regulation and downstream signaling (PMID:9407060). Recognition of somatic RHOA mosaicism is essential for accurate molecular diagnosis and informs tissue‐targeted sequencing strategies.

Key Take-home: Somatic mosaic RHOA c.139G>A (p.Glu47Lys) is a disease‐defining biomarker for EDFAOB and should prompt biopsy of affected skin when germline testing is uninformative.

References

• American journal of medical genetics. Part A • 2025 • From Clinical Observation to Genetic Confirmation: Somatic Mosaic Mutations in RHOA on Ectodermal Dysplasia With Multi-System Involvement PMID:39564940
• The Journal of biological chemistry • 1997 • Structural determinants required for the interaction between Rho GTPase and the GTPase-activating domain of p190 PMID:9407060

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