July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy
Author Affiliations & Notes
  • Carlo Rivolta
    Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
    Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
  • Footnotes
    Commercial Relationships   Carlo Rivolta, None
  • Footnotes
    Support  Swiss National Science Foundation grant #176097
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 426. doi:
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      Carlo Rivolta; A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):426.

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

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Purpose : To understand the reasons for missing heritability in hereditary retinal degenerations (HRDs) and analyze the inheritance pattern of specific forms of RP1-linked retinal dystrophy in the Japanese population.

Methods : Whole-genome sequencing, whole-exome sequencing, direct Sanger sequencing, SNP-chip hybridization.

Results : A large-scale sequencing effort in Japanese HRD patients identified three variants in the RP1 gene: an Alu element insertion in exon 4 (m1, c.4052_4053ins328), a frameshift (m2, c.4196del), and a nonsense (m3, c.5797C>T). These alleles segregated as Mendelian, recessive mutations in 12 unrelated families, with patients presenting with m1/m1, m1/m2, or m1/m3 genotypes.
Surprisingly, m3 was not a rare allele, as it was detected in the general population with a frequency of 0.6%, and direct screening of more than 12,000 Japanese individuals revelated the presence of 3 homozygotes (m3/m3) and 142 heterozygotes (m3/+), who displayed no signs of retinal disease. However, patients vs. controls comparison showed that m3 was significanlty enriched in patients (frequency = 2.1%, i.e. a 3.5-fold enrichment; p-value = 1.29x10-6), indicating that, despite being benign in homozygosis or heterozygosis, this variant was not neutral with respect to retinal health.
We therefore reasoned that m3 could be pathogenic following a non-Mendelian mode of inheritance and performed ExWAS in 10 patients carrying m3/+ vs. 3,554 Japanese controls from the 3.5KJPN database. This test identified one variant in the ciliary gene KIF13B (c.834-35T>C, rs117338543) that was significantly enriched in patients. This association was replicated in 21 additional patients with the same genotype and 125 controls from the JGA-NGS dataset, providing a combined 6-fold enrichment for rs117338543 in patients vs. controls.

Conclusions : Our data show that, despite introducing a premature stop codon in the RP1 open reading frame, the m3 variant does not cause disease in heterozygous or homozygous carriers. However, this same change may act as a pathogenic allele in a Mendelian fashion (with another RP1 mutation in trans), or in association with rare variants in at least another gene, according to a non-Mendelian pattern. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a new genetic model linking monogenic and complex inheritance

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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