PP05.10 – 3086: Cockayne syndrome and DNA repair disorders: Novel expanding neurological phenotype

Abstract

Objective Cockayne syndrome is an autosomal recessive leukodystrophy and multisystem disorder characterized by mental retardation, microcephaly, severe growth failure, sensorial impairment, peripheral neuropathy and cutaneous photosensitivity. It belongs to the family of DNA repair and transcription disorders together with xeroderma pigmentosum and trichothiodystrophy. Clinical and genetic diagnosis still remains challenging. Our goal was to develop a unique and efficient mutation-screening strategy for Cockayne syndrome and related disorders and to improve our understanding of the clinical spectrum of these conditions. Methods We have designed a novel targeted high-throughput sequencing approach for the diagnosis of Cockayne syndrome and related DNA repair disorders. We have studied 30 patients presenting with the cardinal clinical features of Cockayne syndrome or related DNA repair disorders. Results We have identified the causative mutations in 14 of the 30 patients. Three patients showed biallelic mutations in the ERCC6/CSB gene, 2 patients in the ERCC8/CSA gene, 1 patient in the ERCC2/XPD gene, 1 patient in the ERCC3/XPB, 1 patient in the ERCC5/XPG, 6 in the POLH gene. We present the clinical, neurological and radiological phenotypes of these patients with regard to our experience of a well-characterized cohort of more than 100 Cockayne patients previously studied in our center and we discuss the implications for diagnosis and prognosis purposes. Conclusion This novel approach enables us to rapidly confirm the genetic diagnosis of Cockayne syndrome and related disoders and to unravel the molecular defect in atypical and overlapping clinical presentations.