More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations

Abstract Background Infant death in KID syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. Objective To discover characteristics that account for poor outcomes in lethal KID syndrome. Methods We collected four new cases and nine previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. Results Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those two “lethal” mutations is likely multifactorial: during life all had at least one serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central CO 2 sensing of GJB2 p.A88V. Limitations Clinical review was retrospective. Conclusion GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electro-physiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All KID syndrome patients may have subtle abnormalities beyond eyes, ears and skin. Early genotyping of KID syndrome births will inform prognostic discussion.