Dataset Information

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.

ABSTRACT: Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency?=?0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency?=?2.1%, i.e., a 3.5-fold enrichment; p-value?=?9.2?×?10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

SUBMITTER: Nikopoulos K

PROVIDER: S-EPMC6599023 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.

Nikopoulos Konstantinos K Cisarova Katarina K Quinodoz Mathieu M Koskiniemi-Kuendig Hanna H Miyake Noriko N Farinelli Pietro P Rehman Atta Ur AU Khan Muhammad Imran MI Prunotto Andrea A Akiyama Masato M Kamatani Yoichiro Y Terao Chikashi C Miya Fuyuki F Ikeda Yasuhiro Y Ueno Shinji S Fuse Nobuo N Murakami Akira A Wada Yuko Y Terasaki Hiroko H Sonoda Koh-Hei KH Ishibashi Tatsuro T Kubo Michiaki M Cremers Frans P M FPM Kutalik Zoltán Z Matsumoto Naomichi N Nishiguchi Koji M KM Nakazawa Toru T Rivolta Carlo C

Nature communications 20190628 1

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly ...[more]

PMID: 31253780

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Project description:Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

Dataset Information

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.

Publications

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.

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