Co-occurring DMD, GJA1, and novel FYCO1 variants in a proband from a consanguineous oculodentodigital dysplasia family: a rare multi-locus case report

Whole-exome sequencing of the proband and the family revealed multi-locus pathogenic variants (MGVs) leading to multiple genetic diagnoses (MGDs), explaining the complex phenotype with neuromuscular, ocular, and craniofacial abnormalities. The proband harbored a <i>de novo</i> hemizygous <i>DMD</i> frameshift variant consistent with Duchenne muscular dystrophy, a paternally inherited heterozygous <i>GJA1</i> in-frame indel associated with oculodentodigital dysplasia (ODDD), and a novel homozygous <i>FYCO1</i> nonsense variant causing congenital cataract. Fraction of ROH (FROH) analyses indicated extended autozygosity, which is indicative of second-cousin-level consanguinity. The novel <i>FYCO1</i> variant was located within one of the indicative ROHs, supporting identity by descent. Structural analysis predicted truncating or domain-disrupting effects across all three genes, aligning with the multisystem phenotype. The coexistence of the <i>DMD</i>, <i>GJA1</i>, and novel <i>FYCO1</i> variants in a single individual is exceptionally rare. To our knowledge, this represents the first report of such a multi-locus combination, highlighting the diagnostic complexity of combined recessive, dominant, and <i>de novo</i> events in a proband born in a consanguineous ODDD family.