Discovery of a Novel CHD7 CHARGE Syndrome Variant by Integrated Omics Analyses
| Autor: | Matthew L. Tedder, Dustin Baldridge, Kathleen Sisco, F S Cole, Jorge L. Granadillo, Bekim Sadikovic, Marcia C. Willing, Alexander J. Paul, Daniel J. Wegner, Jennifer A. Wambach |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proband Genetics CHARGE syndrome epigenetics Optic disk 030105 genetics & heredity Biology medicine.disease DNA sequencing Article CHD7 genome sequencing 03 medical and health sciences 030104 developmental biology Gene duplication medicine Haploinsufficiency Exome exome sequencing Genetics (clinical) Exome sequencing |
| Zdroj: | Am J Med Genet A Paediatrics Publications |
| Popis: | Chromodomain helicase DNA-binding protein 7 (CHD7) pathogenic variants are identified in more than 90% of infants and children with CHARGE (Coloboma of the iris, retina, and/or optic disk; congenital Heart defects, choanal Atresia, Retardation of growth and development, Genital hypoplasia, and characteristic outer and inner Ear anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, CHD7 sequencing and deletion/duplication analysis, SEMA3E sequencing, and trio exome and whole-genome sequencing (WGS). We used a comprehensive clinical assessment, genome-wide methylation analysis (GMA), reanalysis of WGS data, and CHD7 RNA studies to discover a novel variant that causes CHD7 haploinsufficiency. The 7-year-old Hispanic male proband has typical phenotypic features of CHARGE syndrome. GMA revealed a CHD7-associated epigenetic signature. Reanalysis of the WGS data with focused bioinformatic analysis of CHD7 detected a novel, de novo 15 base pair deletion in Intron 4 of CHD7 (c.2239-20_2239-6delGTCTTGGGTTTTTGT [NM_017780.3]). Using proband RNA, we confirmed that this novel deletion causes CHD7 haploinsufficiency by disrupting the canonical 3' splice site and introducing a premature stop codon. Integrated genomic, epigenomic, and transcriptome analyses discovered a novel CHD7 variant that causes CHARGE syndrome. |
| Databáze: | OpenAIRE |
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