Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.
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.
McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
Emilie
E
Lalonde
Steffen
S
Albrecht
Kevin C H
KC
Ha
Karine
K
Jacob
Nathalie
N
Bolduc
Constantin
C
Polychronakos
Pierre
P
Dechelotte
Jacek
J
Majewski
Nada
N
Jabado
D000015:Abnormalities, Multiple / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D009154:Mutation / Q000235:genetics*; D015203:Reproducibility of Results; D013577:Syndrome