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

Area of Science:

• Genetics
• Pediatrics
• Dermatology

Background:

• Keratitis-Ichthyosis-Deafness (KID) syndrome is a rare genetic disorder.
• Infant mortality in KID syndrome is recognized but poorly understood.
• The association between specific genotypes and pathophysiology of lethal KID syndrome requires further investigation.

Purpose of the Study:

• To identify clinical characteristics associated with poor outcomes in lethal KID syndrome.
• To investigate the genetic basis of early lethality in KID syndrome.
• To understand the pathophysiology of fatal KID syndrome cases.

Main Methods:

• Retrospective analysis of 4 new and 9 previously reported lethal KID syndrome cases.
• Genotyping of all studied lethal KID syndrome cases.
• Molecular modeling of GJB2 p.A88V and GJB2 p.G45E mutants.

Main Results:

• The GJB2 p.G45E and p.A88V mutations were uniformly associated with infant death.
• Patients with these mutations experienced multifactorial complications including severe infections, poor weight gain, and respiratory distress.
• Molecular modeling of GJB2 p.G45E did not reveal an impact on the salt bridge implicated in CO2 sensing abnormalities for GJB2 p.A88V.

Conclusions:

• GJB2 p.G45E and p.A88V are the sole KID syndrome mutations linked to consistent early lethality.
• These severe GJB2 mutations manifest as multi-organ abnormalities in lethal KID syndrome.
• Early genetic testing for KID syndrome is recommended for prognostic discussions.