1. The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects
- Author
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Han G. Brunner, Ephrat Levy-Lahad, Chris Tyler-Smith, Massimo Mezzavila, Christian Gilissen, Reedik Mägi, Andres Metspalu, Yali Xue, Reidar Andreson, Shai Carmi, Hila Fridman, Helger G. Yntema, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)
- Subjects
Male ,at-risk couples ,autosomal recessive disorders ,carrier frequency ,pre-conception carrier screening ,selection ,Cohort Studies ,Europe ,Exome ,Female ,Genes, Recessive ,Genetic Testing ,Genetic Variation ,Health ,Heterozygote ,Humans ,Intellectual Disability ,Whites ,Consanguinity ,Family Characteristics ,Phenotype ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Genetics (clinical) ,Genetics ,0303 health sciences ,education.field_of_study ,030305 genetics & heredity ,Genetic disorder ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,GENOME ,GENES ,GENETICS ,Population ,Biology ,Article ,White People ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Recessive ,Allele ,education ,Gene ,030304 developmental biology ,Carrier signal ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,MUTATIONS ,medicine.disease ,Genetic architecture - Abstract
The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 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.
- Published
- 2021
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