WDR35 mutation in siblings with Sensenbrenner syndrome: A ciliopathy with variable phenotype

Authors

  • Carlos A. Bacino,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Texas Children's Hospital, Houston, Texas
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  • Shweta U. Dhar,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Department of Medicine, Baylor College of Medicine, Houston, Texas
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  • Nicola Brunetti-Pierri,

    1. Telethon Institute of Genetics and Medicine, Naples, Italy
    2. Department of Pediatrics, Federico II University of Naples, Italy
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  • Brendan Lee,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Howard Hughes Medical Institute, Frederick, Maryland
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  • Penelope E. Bonnen

    Corresponding author
    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
    • Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Mailstop BCM226, Houston, TX 77030.
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  • Conflicts of interest: PEB is on the clinical advisory board for Locus Development, Inc.

  • How to Cite this Article: Bacino CA, Dhar SU, Brunetti-Pierri N, Lee B, Bonnen PE. 2012. WDR35 mutation in siblings with Sensenbrenner syndrome: A ciliopathy with variable phenotype. Am J Med Genet Part A 158A: 2917–2924.

Abstract

Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepatic fibrosis leading to liver failure and early death in two of the children. Both parents were unaffected suggesting autosomal recessive inheritance. The family and their affected children were followed over a decade. Exome sequencing was performed in one affected individual. It showed a homozygous missense mutation in a highly conserved position of the WDR35 gene. This family represents a WDR35-ciliopathy with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified SRPs. The accurate molecular diagnosis of this family exemplifies the power of exome sequencing in the diagnosis of Mendelian disorders and enabled us to broaden and refine our understanding of Sensenbrenner syndrome and SRP. Detailed genotype–phenotype information is provided as well as discussion of previously reported cases. © 2012 Wiley Periodicals, Inc.

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