Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing

Authors

  • Emilie Lalonde,

    1. McGill University and Genome Quebec Innovation Centre, Montreal, Canada
    2. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
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  • Steffen Albrecht,

    1. Department of Pathology, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada
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  • Kevin C.H. Ha,

    1. McGill University and Genome Quebec Innovation Centre, Montreal, Canada
    2. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
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  • Karine Jacob,

    1. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
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  • Nathalie Bolduc,

    1. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
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  • Constantin Polychronakos,

    1. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
    2. Departments of Pediatrics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada
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  • Pierre Dechelotte,

    1. Department of Pathological Anatomy, CHU Clermont–Ferrand, Université d'Auvergne, France
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  • Jacek Majewski,

    1. McGill University and Genome Quebec Innovation Centre, Montreal, Canada
    2. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
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  • Nada Jabado

    Corresponding author
    1. Departments of Human Genetics, McGill University Health Center, Montreal, Canada
    2. Departments of Pediatrics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada
    • Montreal Children's Hospital Research Institute, 4060 Ste. Catherine West, PT-239, Montreal, Qc, Canada H3Z 2Z3
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  • Communicated by Graham R. Taylor

  • The first two authors equally contributed to the manuscript.

Abstract

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.

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