A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome

• Published in: Scientific reports Vol. 7; no. 1; p. 44271
• Main Authors: Xie, Hua, Li, Xiaoyan, Peng, Jiping, Chen, Qian, Gao, ZhiJie, Song, Xiaozhen, Li, WeiYu, Xiao, Jianqiu, Li, Caihua, Zhang, Ting, Gusella, James F., Zhong, Jianmin, Chen, Xiaoli
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.03.2017; Nature Publishing Group
• Subjects: 631/208/2489/1512; 692/308/2056; Adolescent; Asian Continental Ancestry Group; Base Sequence; Breakpoints; Child, Preschool; Cockayne syndrome; Cockayne Syndrome - diagnosis; Cockayne Syndrome - ethnology; Cockayne Syndrome - genetics; Cockayne Syndrome - pathology; Comparative Genomic Hybridization; DNA Repair Enzymes - deficiency; DNA Repair Enzymes - genetics; Exons; Female; Gene Expression; Genetic screening; Hereditary diseases; Heterozygosity; Humanities and Social Sciences; Humans; Hybridization; Male; Middle Aged; multidisciplinary; Neurological complications; Pedigree; Phenotype; Physical growth; Polymerase chain reaction; RNA Splicing; Science; Sequence Deletion; Siblings; Splicing; Transcription Factors - deficiency; Transcription Factors - genetics; Whole Exome Sequencing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep44271

Cockayne syndrome is an autosomal recessive disorder principally characterized by postnatal growth failure and progressive neurological dysfunction, due primarily to mutations in ERCC6 and ERCC8. Here, we report our diagnostic experience for two patients in a Chinese family suspected on clinical grounds to have Cockayne syndrome. Using multiple molecular techniques, including whole exome sequencing, array comparative genomic hybridization and quantitative polymerase chain reaction, we identified compound heterozygosity for a maternal splicing variant (chr5:60195556, NM_000082:c.618-2A > G) and a paternal complex deletion/inversion/deletion rearrangement removing exon 4 of ERCC8, confirming the suspected pathogenesis in these two subjects. Microhomology (TAA and AGCT) at the breakpoints indicated that microhomology-mediated FoSTeS events were involved in this complex ERCC8 rearrangement. This diagnostic experience illustrates the value of high-throughput genomic technologies combined with detailed phenotypic assessment in clinical genetic diagnosis.