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

## TL;DR

A rare case report describes a patient with multiple genetic variants causing complex neuromuscular, ocular, and facial abnormalities.

## Contribution

This is the first report of a multi-locus combination of DMD, GJA1, and novel FYCO1 variants in a consanguineous family.

## Key findings

- The proband had three pathogenic variants in DMD, GJA1, and FYCO1, explaining a complex multisystem phenotype.
- FROH analysis indicated consanguinity, with the FYCO1 variant located in an autozygous region.
- Structural analysis confirmed the variants' disruptive effects, aligning with the observed clinical features.

## 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.