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Ciliary Genes TBC1D32/C6orf170 and SCLT1 are Mutated in Patients with OFD Type IX

Authors

  • Nouran Adly,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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    • These two authors have contributed equally and should be considered as co-first authors.

  • Amal Alhashem,

    1. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
    2. Patterns of Fetal Malformations in The Saudi Population Group, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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    • These two authors have contributed equally and should be considered as co-first authors.

  • Amer Ammari,

    1. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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  • Fowzan S. Alkuraya

    Corresponding author
    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    2. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
    • Correspondence to: Fowzan S. Alkuraya, Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, MBC-03 PO BOX 3354, Riyadh 11211, Saudi Arabia. E-mail: falkuraya@kfshrc.edu.sa

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  • Contract grant sponsor: DHFMR Collaborative Research Grant (FSA).

  • Communicated by Garry R. Cutting

ABSTRACT

Clinical syndromes caused by defects in the primary cilium are heterogeneous but there are recurrent phenotypic manifestations that define them as a collective group known as ciliopathies. Dozens of genes have been linked to various ciliopathies but large patient cohorts have clearly revealed the existence of additional genetic heterogeneity, which is yet to be fully appreciated. In our search for novel ciliopathy-linked genes through the study of unmapped ciliopathy phenotypes, we have identified two simplex cases with a severe ciliopathy phenotype consistent with oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia. In addition, there was variable presence of polydactyly, absent pituitary, and congenital heart disease. The autozygome of each index harbored a single novel truncating variant as revealed by exome sequencing, and the affected genes (SCLT1 and TBC1D32/C6orf170) have established roles in centrosomal biology and ciliogenesis. Our findings suggest a previously unrecognized role of SCLT1 and TBC1D32 in the pathogenesis of ciliopathy in humans.

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