The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects
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 v...
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| Veröffentlicht in: | American journal of human genetics 2021-04, Vol.108 (4), p.608-619 |
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| creator | Fridman, Hila Yntema, Helger G. Mägi, Reedik Andreson, Reidar Metspalu, Andres Mezzavilla, Massimo Tyler-Smith, Chris Xue, Yali Carmi, Shai Levy-Lahad, Ephrat Gilissen, Christian Brunner, Han G. |
| description | 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. |
| doi_str_mv | 10.1016/j.ajhg.2021.03.004 |
| format | Article |
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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.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2021.03.004</identifier><identifier>PMID: 33740458</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>at-risk couples ; autosomal recessive disorders ; carrier frequency ; Cohort Studies ; Consanguinity ; Europe - ethnology ; European Continental Ancestry Group - genetics ; Exome - genetics ; Family Characteristics ; Female ; Genes, Recessive - genetics ; Genetic Testing ; Genetic Variation - genetics ; Health ; Heterozygote ; Humans ; Intellectual Disability - genetics ; Male ; Phenotype ; pre-conception carrier screening ; selection</subject><ispartof>American journal of human genetics, 2021-04, Vol.108 (4), p.608-619</ispartof><rights>2021 American Society of Human Genetics</rights><rights>Copyright © 2021 American Society of Human Genetics. 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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.</description><subject>at-risk couples</subject><subject>autosomal recessive disorders</subject><subject>carrier frequency</subject><subject>Cohort Studies</subject><subject>Consanguinity</subject><subject>Europe - ethnology</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Exome - genetics</subject><subject>Family Characteristics</subject><subject>Female</subject><subject>Genes, Recessive - genetics</subject><subject>Genetic Testing</subject><subject>Genetic Variation - genetics</subject><subject>Health</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Intellectual Disability - genetics</subject><subject>Male</subject><subject>Phenotype</subject><subject>pre-conception carrier screening</subject><subject>selection</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU2L1TAUhoMoznX0D7iQLN20niRN2wsiyDB-wICbcR3S9OQ2l94kJm1h_r253HHQjasQ8rxvDuch5C2DmgFrPxxrfZwONQfOahA1QPOM7JgUXdW2IJ-THQDwas_33RV5lfMRgLEexEtyJUTXQCP7Hcn3E9JZ-zEbHZEGS_W6hBxOeq4SGszZbUijXqZwQO8M3XRy2i-ZOk9v1xQiak9jiOusFxd8pgk31HOmcUIfloeIVY5onC1ZtBbNkl-TF7YQ-ObxvCY_v9ze33yr7n58_X7z-a4yjZRL1UrkArU1Qz9wjfvRctlLblpE3fG243bPhR6h5TBI02FX7lqIkXUNa-zQiWvy6dIb1-GEo0G_JD2rmNxJpwcVtFP_vng3qUPYVA9yL4QsBe8fC1L4tWJe1Mllg3PZF4Y1Ky5BNI1kLS8ov6AmhZwT2qdvGKizLXVUZ1vqbEuBUMVWCb37e8CnyB89Bfh4AbCsaXOYVDYOvcHRFTmLGoP7X_9vQJSqgA</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Fridman, Hila</creator><creator>Yntema, Helger G.</creator><creator>Mägi, Reedik</creator><creator>Andreson, Reidar</creator><creator>Metspalu, Andres</creator><creator>Mezzavilla, Massimo</creator><creator>Tyler-Smith, Chris</creator><creator>Xue, Yali</creator><creator>Carmi, Shai</creator><creator>Levy-Lahad, Ephrat</creator><creator>Gilissen, Christian</creator><creator>Brunner, Han G.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1693-9699</orcidid></search><sort><creationdate>20210401</creationdate><title>The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects</title><author>Fridman, Hila ; 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| subjects | at-risk couples autosomal recessive disorders carrier frequency Cohort Studies Consanguinity Europe - ethnology European Continental Ancestry Group - genetics Exome - genetics Family Characteristics Female Genes, Recessive - genetics Genetic Testing Genetic Variation - genetics Health Heterozygote Humans Intellectual Disability - genetics Male Phenotype pre-conception carrier screening selection |
| title | The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects |
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