June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Homozygosity mapping-guided exome sequencing in LCA patients of consanguineous origin reveals mutations in known genes and a novel candidate gene.
Author Affiliations & Notes
  • Basamat Almoallem
    Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent , Belgium
    Department of Ophthalmology, King Abdul-Aziz University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  • Kristof Van Schil
    Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent , Belgium
  • Laila Jeddawi
    Pediatric Ophthalmology Division, Dhahran Eye Specialist Hospital, Dhahran, Saudi Arabia
  • Bart Peter Leroy
    Department of Ophthalmology, Ghent University Hospital, Ghent , Belgium
    Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent , Belgium
  • Frauke Coppieters
    Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent , Belgium
  • Elfride De Baere
    Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent , Belgium
  • Footnotes
    Commercial Relationships   Basamat Almoallem, None; Kristof Van Schil, None; Laila Jeddawi, None; Bart Leroy, None; Frauke Coppieters, None; Elfride De Baere, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1242. doi:
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      Basamat Almoallem, Kristof Van Schil, Laila Jeddawi, Bart Peter Leroy, Frauke Coppieters, Elfride De Baere; Homozygosity mapping-guided exome sequencing in LCA patients of consanguineous origin reveals mutations in known genes and a novel candidate gene.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1242.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Leber congenital amaurosis (LCA) is the most severe autosomal recessive inherited retinal dystrophy (IRD) accounting for 5% of childhood blindness. To date, 70% of LCA cases can be explained by mutations in one of the 23 known LCA genes. Here we aimed to identify the underlying genetic cause of LCA in 15 Saudi-Arabian families with reported or suspected consanguinity.

Methods : A total of 20 probands, ranging between 2-9 years old, were clinically diagnosed with LCA or early-onset IRD. The genetic workup consisted of homozygosity mapping followed by targeted next generation sequencing (NGS) or Sanger sequencing, combined or not with whole exome sequencing (WES). Co-segregation could be demonstrated for all identified mutations.

Results : Overall, we identified 13 putative pathogenic homozygous mutations in 10 known IRD genes in 14/15 (93.3%) of the studied families, six of which are novel. Eight of these genes were known LCA genes: CRB1 (3/15, 20%), RPGRIP1 (2/15, 13.3%), SPATA7 (2/15, 13.3 %) and CABP4, CEP290, GUCY2D, MERTK, RDH12 (1/15, 6.7% for the latter five) respectively. Specifically, the recurrent RPGRIP1 mutation c.1007delA p.(Glu370Asnfs*5) is a reported potential founder mutation in the Saudi population (Khan et al. 2014). Moreover, mutations were found in ATF6 and ALMS1 (1/15, 6.7% for each), known to be implicated in autosomal recessive achromatopsia and in Alström syndrome, respectively. In two affected sibs with LCA and autism, we identified a novel nonsense mutation c.3283C>T p.(Arg1095*) in the Regulating Synaptic Membrane Exocytosis 2 (RIMS2) gene (NM_001100117.2), located in the largest autozygous region of 25 Mb. RIMS2 was found to be expressed in human retina and in cerebral cortex, which might be consistent with the phenotype observed in the sibship. A mutation in a paralog RIMS1 was previously reported in autosomal dominant cone-rod dystrophy (CORD7; MIM 603649), implicating a protein with a synaptic function in retinal disease.

Conclusions : We identified 14 putative pathogenic mutations in all studied LCA families, demonstrating the power of autozygome-guided WES in a genetically heterogeneous consanguineous IRD cohort. Apart from mutations in known IRD genes (14/15; 93.3%), we uncovered RIMS2 as a potential novel LCA gene.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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