Abstract
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 de novo hemizygous DMD frameshift variant consistent with Duchenne muscular dystrophy, a paternally inherited heterozygous GJA1 in-frame indel associated with oculodentodigital dysplasia (ODDD), and a novel homozygous FYCO1 nonsense variant causing congenital cataract. Fraction of ROH (FROH) analyses indicated extended autozygosity, which is indicative of second-cousin-level consanguinity. The novel FYCO1 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 DMD, GJA1, and novel FYCO1 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 de novo events in a proband born in a consanguineous ODDD family.