Danyan Zhang1, Limeng Dai2, Zhenhua Zhou3, Jun Hu3, Yun Bai4, Hong Guo5. 1. Department of Medical Genetics, College of Basic Medicine, Army Medical University (Third Military Medical University), 30#, Gaotanyan St., Shapingba District, Chongqing 400038, PR China; Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission (Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, 18#, Honghuang Road, Jiangbei District, Chongqing 400020, PR China. 2. Department of Medical Genetics, College of Basic Medicine, Army Medical University (Third Military Medical University), 30#, Gaotanyan St., Shapingba District, Chongqing 400038, PR China. 3. Department of Neurology, Southwest Hospital, Army Medical University (Third Military Medical University), 30#, Gaotanyan St., Shapingba District, Chongqing 400038, PR China. 4. Department of Medical Genetics, College of Basic Medicine, Army Medical University (Third Military Medical University), 30#, Gaotanyan St., Shapingba District, Chongqing 400038, PR China. Electronic address: yunbai@tmmu.edu.cn. 5. Department of Medical Genetics, College of Basic Medicine, Army Medical University (Third Military Medical University), 30#, Gaotanyan St., Shapingba District, Chongqing 400038, PR China. Electronic address: guohong02@gmail.com.
Abstract
BACKGROUND: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. METHODS: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. ERCC8 mutations and phenotypes were examined. RESULTS: All three patients presented cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. Whole genome and candidate region linkage analysis in the consanguineous family revealed a maximum logarithm of the odds score at 5q12.1. This homozygous region was confirmed by homozygosity mapping. The pathogenic missense mutation p.Gly257Arg affecting an evolutionary highly conserved amino acid was identified in ERCC8 at 5q12.1. Integrated application of whole exome sequencing and homozygosity mapping is an efficient approach for gene mapping and mutation identification in consanguineous families. CONCLUSIONS: We identified a novel ERCC8 mutation and new unique disease phenotype. These results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings.
BACKGROUND: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. METHODS: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. ERCC8 mutations and phenotypes were examined. RESULTS: All three patients presented cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. Whole genome and candidate region linkage analysis in the consanguineous family revealed a maximum logarithm of the odds score at 5q12.1. This homozygous region was confirmed by homozygosity mapping. The pathogenic missense mutation p.Gly257Arg affecting an evolutionary highly conserved amino acid was identified in ERCC8 at 5q12.1. Integrated application of whole exome sequencing and homozygosity mapping is an efficient approach for gene mapping and mutation identification in consanguineous families. CONCLUSIONS: We identified a novel ERCC8 mutation and new unique disease phenotype. These results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings.
Authors: Nguyen Thuy Duong; Tran Huu Dinh; Britta S Möhl; Stefan Hintze; Do Hai Quynh; Duong Thi Thu Ha; Ngo Diem Ngoc; Vu Chi Dung; Noriko Miyake; Nong Van Hai; Naomichi Matsumoto; Peter Meinke Journal: Aging (Albany NY) Date: 2022-06-22 Impact factor: 5.955