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Preprints, Working Papers, ... Heterogeneous clinical features in Cockayne syndrome-A patients with the same mutation and in siblings Year : 2021

Heterogeneous clinical features in Cockayne syndrome-A patients with the same mutation and in siblings

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Abstract

Background Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC6/CSB or ERCC8/CSA that participate in transcription-coupled nucleotide excision repair (TC-NER) of UV-induced DNA damage. CS patients display a large heterogeneity of clinical symptoms and severities, the reason of which is not fully understood, and little data is available for affected siblings. CS is largely undiagnosed in North Africa. Methods We report here the clinical description as well as genetic and functional characterization of eight North African CS patients, including siblings. These patients, who belonged to six unrelated families, underwent complete clinical examination and biochemical analyses. Sanger sequencing was performed for the recurrent mutation in five families, and targeted gene sequencing for one patient of the other family. We also performed RRS (Recovery RNA Synthesis) to confirm the functional impairment of DNA repair in the identified mutations. Results Six out of eight patients carried a homozygous indel mutation (c.598_600delinsAA) in exon 7 of ERCC8, and displayed a variable clinical spectrum, including between siblings, despite sharing the same mutation. The other two patients were Tunisian siblings who carried a homozygous splice-site variant in ERCC8 (c.843 + 1 G > C). They presented more severe clinical manifestations, which are in general rarely associated with CSA mutations, leading to gastrostomy and hepatic damage. Impaired TC-NER was confirmed by RRS in six tested patients. Conclusions This study provides the first deep characterization of case series of rare CS-A patients in North Africa. They carry mutations described to date only in this region and the Middle-East. We also provide the largest characterization of unrelated patients, as well as siblings, with the same mutation, providing a framework for dissecting elusive genotype-phenotype correlations in CS.
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Dates and versions

pasteur-03548783 , version 1 (31-01-2022)

Licence

Attribution - CC BY 4.0

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Asma Chikhaoui, Ichraf Kraoua, Nadège Calmels, Sami Bouchoucha, Cathy Obringer, et al.. Heterogeneous clinical features in Cockayne syndrome-A patients with the same mutation and in siblings. 2022. ⟨pasteur-03548783⟩
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