The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

H. Fridman; H.G. Yntema; R. Magi; R. Andreson; A. Metspalu; M. Mezzavila; C. Tyler-Smith; Y.L. Xue; S. Carmi; E. Levy-Lahad; C. Gilissen; H.G. Brunner

doi:10.1016/j.ajhg.2021.03.004

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

H. Fridman, H.G. Yntema, R. Magi, R. Andreson, A. Metspalu, M. Mezzavila, C. Tyler-Smith, Y.L. Xue, S. Carmi, E. Levy-Lahad, C. Gilissen^*, H.G. Brunner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

Original language	English
Pages (from-to)	608-619
Number of pages	12
Journal	American Journal of Human Genetics
Volume	108
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2021.03.004
Publication status	Published - 1 Apr 2021

Keywords

GENOME
MUTATIONS
GENETICS
GENES

Access to Document

10.1016/j.ajhg.2021.03.004Licence: Free access - publisher

https://www.biorxiv.org/content/biorxiv/early/2020/11/17/2020.11.16.384206.full.pdf

Cite this

Fridman, H., Yntema, H. G., Magi, R., Andreson, R., Metspalu, A., Mezzavila, M., Tyler-Smith, C., Xue, Y. L., Carmi, S., Levy-Lahad, E., Gilissen, C., & Brunner, H. G. (2021). The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects. American Journal of Human Genetics, 108(4), 608-619. https://doi.org/10.1016/j.ajhg.2021.03.004

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abstract = "The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.",

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Fridman, H, Yntema, HG, Magi, R, Andreson, R, Metspalu, A, Mezzavila, M, Tyler-Smith, C, Xue, YL, Carmi, S, Levy-Lahad, E, Gilissen, C & Brunner, HG 2021, 'The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects', American Journal of Human Genetics, vol. 108, no. 4, pp. 608-619. https://doi.org/10.1016/j.ajhg.2021.03.004

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T1 - The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

AU - Fridman, H.

AU - Yntema, H.G.

AU - Magi, R.

AU - Andreson, R.

AU - Metspalu, A.

AU - Mezzavila, M.

AU - Tyler-Smith, C.

AU - Xue, Y.L.

AU - Carmi, S.

AU - Levy-Lahad, E.

AU - Gilissen, C.

AU - Brunner, H.G.

PY - 2021/4/1

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N2 - The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

AB - The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

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