Identification and Characterization of a Novel Recurrent ERCC6 Variant in Patients with a Severe Form of Cockayne Syndrome B

• Published in: Genes 2021-11, Vol.12 (12), p.1922
• Main Authors: Zayoud, Khouloud, Kraoua, Ichraf, Chikhaoui, Asma, Calmels, Nadège, Bouchoucha, Sami, Obringer, Cathy, Crochemore, Clément, Najjar, Dorra, Zarrouk, Sinda, Miladi, Najoua, Laugel, Vincent, Ricchetti, Miria, Turki, Ilhem, Yacoub-Youssef, Houda
• Format: Article
• Language: English
• Subjects: Atrophy; Biopsy; Blotting, Western; Cells, Cultured; Child; Child, Preschool; Cockayne syndrome; Cockayne Syndrome - diagnostic imaging; Cockayne Syndrome - genetics; Cockayne Syndrome - physiopathology; Consanguinity; Disease; DNA biosynthesis; DNA Helicases - genetics; DNA repair; DNA Repair - genetics; DNA Repair Enzymes - genetics; Female; Fibroblasts; Fibroblasts - radiation effects; Founder effect; Gene expression; Genetic analysis; Genetic counseling; Genetics; Genomes; Homozygote; Human genetics; Human health and pathology; Humans; Life Sciences; Magnetic Resonance Imaging; Male; Microcephaly; Mutation; Neurons and Cognition; Next-generation sequencing; Nucleotide excision repair; Patients; Pedigree; Phenotypes; Photosensitivity; Poly-ADP-Ribose Binding Proteins - genetics; Prenatal diagnosis; Proteins; Rare diseases; Siblings; Transcription; Ultraviolet Rays; Western blotting
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes12121922

Cockayne syndrome (CS) is a rare disease caused by mutations in / or / . We report here the clinical, genetic, and functional analyses of three unrelated patients mutated in / with a severe phenotype. After clinical examination, two patients were investigated via next generation sequencing, targeting seventeen Nucleotide Excision Repair (NER) genes. All three patients harbored a novel, c.3156dup, homozygous mutation located in exon 18 of / that affects the C-terminal region of the protein. Sanger sequencing confirmed the mutation and the parental segregation in the three families, and Western blots showed a lack of the full-length protein. NER functional impairment was shown by reduced recovery of RNA synthesis with proficient unscheduled DNA synthesis after UV-C radiations in patient-derived fibroblasts. Despite sharing the same mutation, the clinical spectrum was heterogeneous among the three patients, and only two patients displayed clinical photosensitivity. This novel variant in Tunisian patients suggests a founder effect and has implications for setting-up prenatal diagnosis/genetic counselling in North Africa, where this disease is largely undiagnosed. This study reveals one of the rare cases of CS clinical heterogeneity despite the same mutation. Moreover, the occurrence of an identical homozygous mutation, which either results in clinical photosensitivity or does not, strongly suggests that this classic CS symptom relies on multiple factors.