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Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene

European Journal of Human Genetics volume 29, pages 965–976 (2021)Cite this article

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Abstract

Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene (NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.

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Fig. 1: The c.1621C>T p.(Gln541*) variant in the FYCO1 gene in the Yakut family with congenital cataract.
Fig. 2
Fig. 3: Prevalence of congenital cataract caused by the homozygous с.1621C>T p.(Gln541*) variant in the FYCO1 gene in the Sakha Republic of Russia.
Fig. 4: Structure of the STR haplotypes with variant с.1621C>T p.(Gln541*) in the FYCO1 gene.
Fig. 5: Schematic structure of the protein FYCO1 and known variants associated with congenital cataract in the FYCO1 gene.

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Acknowledgements

We thank all the patients and blood sample donors who contributed to this study. Special thanks to the physicians and tutors of the special boarding school for blind children (Yakutsk, Russia).

Funding

The study was supported by the Project of the Ministry of Science and Higher Education of the Russian Federation (basic part of funding to M.K. Ammosov North-Eastern Federal University #FSRG-2020–0016) and by the Russian Foundation for Basic Research (grants #18–05–600035_Arctika, #19–34–60023_Perspektiva).

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, Yakut Science Centre of Complex Medical Problems, Yakutsk, Russian Federation

    Nikolay A. Barashkov, Fedor M. Teryutin, Aisen V. Solovyev, Vera G. Pshennikova, Georgii P. Romanov, Nyurgun N. Gotovtsev & Sardana A. Fedorova

  2. Laboratory of Molecular Biology, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation

    Nikolay A. Barashkov, Tuyara V. Borisova, Aisen V. Solovyev, Georgii P. Romanov, Elza K. Khusnutdinova & Sardana A. Fedorova

  3. Genomed Ltd, Moscow, Russian Federation

    Fedor A. Konovalov

  4. Department of Ophthalmology, Republican Hospital #1 – National Centre of Medicine, Yakutsk, Russian Federation

    Nadejda V. Sapojnikova & Lyubov S. Vychuzhina

  5. SB RAS Genomics Core Facility, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

    Igor V. Morozov & Alexander A. Bondar

  6. Novosibirsk State University, Novosibirsk, Russian Federation

    Igor V. Morozov & Olga L. Posukh

  7. Medical Institute, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation

    Fedor A. Platonov & Tatiana E. Burtseva

  8. Laboratory of the Children Health Monitoring and Medical-environmental Research, Yakut Science Centre of Complex Medical Problems, Yakutsk, Russian Federation

    Tatiana E. Burtseva

  9. Laboratory of Human Molecular Genetics, Institute of Biochemistry and Genetics, Ufa Federal Research Center of Russian Academy of Sciences, Ufa, Russian Federation

    Elza K. Khusnutdinova

  10. Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russian Federation

    Elza K. Khusnutdinova

  11. Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

    Olga L. Posukh

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  1. Nikolay A. Barashkov
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  2. Fedor A. Konovalov
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  3. Tuyara V. Borisova
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Contributions

Conceived and designed the experiments and wrote the paper: NAB, FAK, TVB, and FMT; performed the experiments: AVS, VGP, NVS, and LSV; analyzed the data: GPR, NNG, IVM, and AAB; collected the samples: FMT, VGP, FAP, and TEB; discussed and proofed the paper: EKK, OLP, and SAF.

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Correspondence to Nikolay A. Barashkov.

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Barashkov, N.A., Konovalov, F.A., Borisova, T.V. et al. Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene. Eur J Hum Genet 29, 965–976 (2021). https://doi.org/10.1038/s41431-021-00833-w

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