Two Truncating MITF Variants Expand the Phenotypic Spectrum of COMMAD Syndrome

Pathogenic variants in MITF (Microphthalmia Transcription Factor) gene are associated with a spectrum of disorders, including Waardenburg syndrome type II and Tietz syndrome. Rare reports suggest that biallelic loss-of-function variants may result in a severe multisystem phenotype. We report an infant presenting with a phenotype consistent with COMMAD-like syndrome (Coloboma, Οsteopetrosis, Μicrophthalmia, Μacrocephaly, Αlbinism, and Deafness) who died in the early neonatal period. In addition to the core COMMAD features, the proband exhibited ectopic ossification, cardiac fibrosis and fibroelastosis, interstitial lung disease, ectopic renal tissue, liver steatosis, and hemosiderosis. Whole-exome sequencing identified two heterozygous truncating MITF variants, the previously reported c.961C>T (p.Arg321Ter) and a novel c.1135A>T (p.Lys379Ter) variant, both predicted to result in impaired MITF function. Parental testing was declined, precluding determination of the phase of the variants. To date, only one study has reported an association between biallelic MITF disruption and a severe clinical phenotype. Our findings provide additional evidence for this genotype-phenotype relationship and further expand the clinical spectrum of COMMAD syndrome. The present case further supports a role for impaired MITF function in the pathogenesis of a severe multisystem phenotype.