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Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next‐generation exome sequencing
Author(s) -
Lalonde Emilie,
Albrecht Steffen,
Ha Kevin C.H.,
Jacob Karine,
Bolduc Nathalie,
Polychronakos Constantin,
Dechelotte Pierre,
Majewski Jacek,
Jabado Nada
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21293
Subject(s) - biology , exome sequencing , genetics , exome , genetic heterogeneity , allelic heterogeneity , compound heterozygosity , dna sequencing , allele , gene , human genetics , phenotype
Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease‐related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., “whole exome”) have the potential to contribute our understanding of human diseases. We used a method for whole‐exome sequencing coupling Agilent whole‐exome capture to the Illumina DNA‐sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular‐receptor‐family member 2, FLVCR2 , which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point‐mutations, insertions‐deletions, and intronic splice‐site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole‐exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients ( n =2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity. Hum Mutat 31:1–6, 2010. © 2010 Wiley‐Liss, Inc.