A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome.
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.
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
Hua
H
Xie
Department of Neurology, Children's Hospital of Jiangxi Province, Jiangxi, China.
Xiaoyan
X
Li
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
Jiping
J
Peng
Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.
Qian
Q
Chen
Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.
ZhiJie
Z
Gao
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
Xiaozhen
X
Song
State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
WeiYu
W
Li
State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
Jianqiu
J
Xiao
Genesky Biotechnologies, ShangHai, China.
Caihua
C
Li
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
Ting
T
Zhang
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.|Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
James F
JF
Gusella
Department of Neurology, Children's Hospital of Jiangxi Province, Jiangxi, China.
Jianmin
J
Zhong
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
Xiaoli
X
Chen
D000293:Adolescent; D044466:Asian People; D001483:Base Sequence; D002675:Child, Preschool; D003057:Cockayne Syndrome / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000235:genetics*; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing; D017384:Sequence Deletion; D035781:Siblings; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D000073359:Exome Sequencing
C095472:ERCC8 protein, human; D014157:Transcription Factors; D045643:DNA Repair Enzymes