ERCC5 novel missense mutation causing developmental delay and spasticity

OBJECTIVE: To describe the phenotype of a novel homozygous missense mutation in the ERCC5 gene. METHODS: Retrospective review of medical records. RESULTS: A 3year8month old boy presented with psychomotor delay noticed during infancy. He was the only child born at term to healthy consanguineous parents (first cousins), weighing 2.5 kg. He had moderate psychomotor delay (walked with support at 15 months and independently around 2 years) and was unable to walk fast at 3years 8months. There was no reported sun-sensitivity or loss of skills. He had subtle facial morphological features (low-set protruding ears, residual pre-axial tag), wide-based crouched gait, central hypotonia, lower limb spasticity and hyperreflexia. There was no microcephaly or growth failure. Eye examination was normal. Magnetic resonance imaging of the brain done when 14 months old showed partial agenesis of corpus callosum, mild global cerebral atrophy, paucity of white matter with delayed myelination. CGH microarray, skeletal survey, abdominal ultrasound, auditory brainstem evoked responses, ophthalmology assessment were normal. Trio whole genome sequencing detected a most probably pathogenic novel homozygous missense variant in the ERCC5 gene inherited from both parents predicted to alter a highly conserved tryptophan residue. CONCLUSIONS: Previous reported cases of Cerebro-oculo-facio-skeletal Syndrome 3 (COFS3) have all been secondary to truncating mutations in the ERCC5 gene. Our case further expands the phenotype of the ERCC5 gene with milder phenotype and overlap with COFS3. Further functional studies are needed to determine the effect of this variant at the protein level and the relation with the phenotype.