Open AccessHypotrichosis with juvenile macular dystrophy: Combination of whole‐genome sequencing and genome‐wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole‐exome sequencing—A lesson from next‐generation sequencing
Author(s) -
Saeidian Amir Hossein,
Vahidnezhad Hassan,
Youssefian Leila,
Sotudeh Soheila,
Sargazi Meisam,
Zeinali Sirous,
Uitto Jouni
Publication year - 2019
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.975
Subject(s) - hypotrichosis , macular dystrophy , genetics , disease gene identification , exome sequencing , biology , whole genome sequencing , missense mutation , genome , gene , phenotype
Background Hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder characterized by abnormal growth of scalp hair and juvenile macular degeneration leading to blindness. We have explored the genetic basis of HJMD in a large consanguineous family with 12 affected patients, 1–76 years of age, with characteristic phenotypes. Methods We first applied genome‐wide homozygosity mapping to 10 affected individuals for linkage analysis to identify the genomic region of the defective gene. All affected individuals shared a 7.2 Mb region of homozygosity on chromosome 16q21‐22.3, which harbored 298 genes, including CDH3 , previously associated with HJMD. However, whole‐exome sequencing (WES) failed to identify the causative mutation in CDH3 . Results Further investigation revealed a missense variant in a gene closely linked to CDH3 (1.4 Mb distance: FHOD1 : c.1306A>G, p.Arg436Gly). This variant was homozygous in all affected individuals and heterozygous in 18 out of 19 obligate carriers. While this variant was found by bioinformatics predictions to be likely pathogenic, a knock‐in mouse for this variant, made by the CRISPR/Cas, showed no disease phenotype. However, using whole‐genome sequencing (WGS), we were able to identify a novel Alu recombination‐mediated deletion in CDH3 :c.del161‐811_246 + 1,044. Conclusion WGS was able to identify a deep intronic deletion mutation, not detected by WES.