en
Scientific article
English

Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families

Published inHuman mutation, vol. 35, no. 10, p. 1203-1210
Publication date2014
Abstract

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

Citation (ISO format)
MAKRYTHANASIS, Periklis et al. Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families. In: Human mutation, 2014, vol. 35, n° 10, p. 1203–1210. doi: 10.1002/humu.22617
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal1059-7794
600views
4downloads

Technical informations

Creation11/26/2014 4:21:00 PM
First validation11/26/2014 4:21:00 PM
Update time03/14/2023 10:18:56 PM
Status update03/14/2023 10:18:55 PM
Last indexation01/16/2024 2:36:23 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack