MICHAUD, Vincent; LASSEAUX, Eulalie; GREEN, David; GERRARD, Dave T; PLAISANT, Claudio; FITZGERALD, Tomas; BIRNEY, Ewan; ARVEILER, Benoit; BLACK, Graeme C; SERGOUNIOTIS, Panagiotis I

doi:10.1038/s41467-022-31392-3

Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

LASSEAUX, Eulalie
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

GREEN, David

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Article de revue

Ce document a été publié dans

Nature Communications. 2022-07-08, vol. 13, n° 1, p. 3939

Résumé en anglais

Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.-301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[-301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.< Réduire

Mots clés en anglais

Albinism

Oculocutaneous

Genotype

Humans

Monophenol Monooxygenase

Mutant Proteins

Pedigree

Phenotype

URI

https://oskar-bordeaux.fr/handle/20.500.12278/183300

DOI

http://dx.doi.org/10.1038/s41467-022-31392-3

Unités de recherche

Maladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211

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The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism.

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Résumé en anglais

Mots clés en anglais

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DOI

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