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

Hila Fridman; Helger G. Yntema; Reedik Mägi; Reidar Andreson; Andres Metspalu; Massimo Mezzavila; Chris Tyler-Smith; Yali Xue; Shai Carmi; Ephrat Levy-Lahad; Christian Gilissen; Han G. Brunner

doi:10.1016/j.ajhg.2021.03.004

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

Hila Fridman, Helger G. Yntema, Reedik Mägi, Reidar Andreson, Andres Metspalu, Massimo Mezzavila, Chris Tyler-Smith, Yali Xue, Shai Carmi, Ephrat Levy-Lahad, Christian Gilissen^*, Han G. Brunner^*

^*Corresponding author for this work

Department of Social Medicine

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

40 Scopus citations

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
State	Published - 1 Apr 2021

Bibliographical note

Publisher Copyright:
© 2021 American Society of Human Genetics

Keywords

at-risk couples
autosomal recessive disorders
carrier frequency
pre-conception carrier screening
selection

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10.1016/j.ajhg.2021.03.004

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Fridman, H., Yntema, H. G., Mägi, R., Andreson, R., Metspalu, A., Mezzavila, M., Tyler-Smith, C., Xue, Y., 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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title = "The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects",

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.",

keywords = "at-risk couples, autosomal recessive disorders, carrier frequency, pre-conception carrier screening, selection",

author = "Hila Fridman and Yntema, {Helger G.} and Reedik M{\"a}gi and Reidar Andreson and Andres Metspalu and Massimo Mezzavila and Chris Tyler-Smith and Yali Xue and Shai Carmi and Ephrat Levy-Lahad and Christian Gilissen and Brunner, {Han G.}",

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Fridman, H, Yntema, HG, Mägi, R, Andreson, R, Metspalu, A, Mezzavila, M, Tyler-Smith, C, Xue, Y, 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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AU - Fridman, Hila

AU - Yntema, Helger G.

AU - Mägi, Reedik

AU - Andreson, Reidar

AU - Metspalu, Andres

AU - Mezzavila, Massimo

AU - Tyler-Smith, Chris

AU - Xue, Yali

AU - Carmi, Shai

AU - Levy-Lahad, Ephrat

AU - Gilissen, Christian

AU - Brunner, Han G.

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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.

KW - at-risk couples

KW - autosomal recessive disorders

KW - carrier frequency

KW - pre-conception carrier screening

KW - selection

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JF - American Journal of Human Genetics

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

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Keywords

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