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Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child
Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child wit...
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| Published in: | European journal of human genetics : EJHG 2021-03, Vol.29 (3), p.455-462 |
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| container_issue | 3 |
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| container_title | European journal of human genetics : EJHG |
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| creator | Mor-Shaked, Hagar Rips, Jonathan Gershon Naamat, Shiri Reich, Avichai Elpeleg, Orly Meiner, Vardiella Harel, Tamar |
| description | Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ
= 8.0565, p value |
| doi_str_mv | 10.1038/s41431-020-00756-y |
| format | article |
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= 8.0565, p value < 0.005). Higher inbreeding coefficient values, calculated from individual exomes, correlated with secondary shared carrier status for diseases of moderate to profound severity (r = 0.17, p value < 0.0125). Our results indicate that consanguineous couples undergoing PGD are at increased risk for a second genetic disease of moderate to profound severity. This study represents an underestimate of the rate of secondary shared carrier status due to inability to detect deep intronic variants, no assessment of copy number variants, and false negative results stemming from stringent variant interpretation. False positive results may result from inaccuracies in public databases. Additional studies in consanguineous populations will determine whether exome-based carrier screening should be recommended to all couples undergoing PGD.</description><identifier>ISSN: 1018-4813</identifier><identifier>EISSN: 1476-5438</identifier><identifier>DOI: 10.1038/s41431-020-00756-y</identifier><identifier>PMID: 33223529</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Adult ; Child ; Classification ; Consanguinity ; Copy number ; Couples ; Diagnosis ; Disease ; Female ; Gene Frequency ; Genes ; Genes, Recessive ; Genetic Carrier Screening - standards ; Genetic Carrier Screening - statistics & numerical data ; Genetic counseling ; Genetic disorders ; Genetic screening ; Genetics ; Genomes ; Hereditary diseases ; Heterozygote ; Humans ; Inbreeding ; Male ; Models, Genetic ; Pedigree ; Phenotype ; Population studies ; Whole Exome Sequencing - statistics & numerical data</subject><ispartof>European journal of human genetics : EJHG, 2021-03, Vol.29 (3), p.455-462</ispartof><rights>The Author(s), under exclusive licence to European Society of Human Genetics 2020.</rights><rights>The Author(s), under exclusive licence to European Society of Human Genetics 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-76def29f5e41f10be943b337a5f49acf85c0329f222f0854b8259e406151c6433</citedby><cites>FETCH-LOGICAL-c430t-76def29f5e41f10be943b337a5f49acf85c0329f222f0854b8259e406151c6433</cites><orcidid>0000-0003-3595-7075</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940654/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940654/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33223529$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mor-Shaked, Hagar</creatorcontrib><creatorcontrib>Rips, Jonathan</creatorcontrib><creatorcontrib>Gershon Naamat, Shiri</creatorcontrib><creatorcontrib>Reich, Avichai</creatorcontrib><creatorcontrib>Elpeleg, Orly</creatorcontrib><creatorcontrib>Meiner, Vardiella</creatorcontrib><creatorcontrib>Harel, Tamar</creatorcontrib><title>Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child</title><title>European journal of human genetics : EJHG</title><addtitle>Eur J Hum Genet</addtitle><description>Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ
= 8.0565, p value < 0.005). Higher inbreeding coefficient values, calculated from individual exomes, correlated with secondary shared carrier status for diseases of moderate to profound severity (r = 0.17, p value < 0.0125). Our results indicate that consanguineous couples undergoing PGD are at increased risk for a second genetic disease of moderate to profound severity. This study represents an underestimate of the rate of secondary shared carrier status due to inability to detect deep intronic variants, no assessment of copy number variants, and false negative results stemming from stringent variant interpretation. False positive results may result from inaccuracies in public databases. Additional studies in consanguineous populations will determine whether exome-based carrier screening should be recommended to all couples undergoing PGD.</description><subject>Adult</subject><subject>Child</subject><subject>Classification</subject><subject>Consanguinity</subject><subject>Copy number</subject><subject>Couples</subject><subject>Diagnosis</subject><subject>Disease</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Genes</subject><subject>Genes, Recessive</subject><subject>Genetic Carrier Screening - standards</subject><subject>Genetic Carrier Screening - statistics & numerical data</subject><subject>Genetic counseling</subject><subject>Genetic disorders</subject><subject>Genetic screening</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Hereditary diseases</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Inbreeding</subject><subject>Male</subject><subject>Models, Genetic</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Population studies</subject><subject>Whole Exome Sequencing - statistics & numerical data</subject><issn>1018-4813</issn><issn>1476-5438</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpdkctOHDEQRa0IFMgkP5BFZIlNNp2UX_3YICFEHhJSWMDa8rjLGaOe9uDqhky-Ph6GoJCVLd9bp1x1GXsv4JMA1X4mLbQSFUioABpTV9tX7Fjopq6MVu1BuYNoK90KdcTeEN0CFLERr9mRUlIqI7tj9vvKZRwnN3D8ldbI3eiGLUXisS_PMUQkTqvi6bl3OUfMnCY3zcRDytxxQp_Gnmf0SBTvkfeRUu6LLY7cp3kzFMBDnFaFzF0I6KcdahWH_i07DG4gfPd0LtjNl4vr82_V5Y-v38_PLiuvFUxVU_cYZBcMahEELLHTaqlU40zQnfOhNR5U0aWUAVqjl600HWqohRG-1kot2Omeu5mXa-x9mSu7wW5yXLu8tclF-1IZ48r-TPe26QqlrHLBPj4BcrqbkSa7juRxGNyIaSYrda3qksJjr5P_rLdpzmWnO1fXNl0NsAPKvcvnRJQxPH9GgN1Fa_fR2gK1j9HabSn68O8YzyV_s1R_AG2WoV8</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Mor-Shaked, Hagar</creator><creator>Rips, Jonathan</creator><creator>Gershon Naamat, Shiri</creator><creator>Reich, Avichai</creator><creator>Elpeleg, Orly</creator><creator>Meiner, Vardiella</creator><creator>Harel, Tamar</creator><general>Nature Publishing Group</general><general>Springer International Publishing</general><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3595-7075</orcidid></search><sort><creationdate>20210301</creationdate><title>Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child</title><author>Mor-Shaked, Hagar ; 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Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ
= 8.0565, p value < 0.005). Higher inbreeding coefficient values, calculated from individual exomes, correlated with secondary shared carrier status for diseases of moderate to profound severity (r = 0.17, p value < 0.0125). Our results indicate that consanguineous couples undergoing PGD are at increased risk for a second genetic disease of moderate to profound severity. This study represents an underestimate of the rate of secondary shared carrier status due to inability to detect deep intronic variants, no assessment of copy number variants, and false negative results stemming from stringent variant interpretation. False positive results may result from inaccuracies in public databases. Additional studies in consanguineous populations will determine whether exome-based carrier screening should be recommended to all couples undergoing PGD.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>33223529</pmid><doi>10.1038/s41431-020-00756-y</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-3595-7075</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Child Classification Consanguinity Copy number Couples Diagnosis Disease Female Gene Frequency Genes Genes, Recessive Genetic Carrier Screening - standards Genetic Carrier Screening - statistics & numerical data Genetic counseling Genetic disorders Genetic screening Genetics Genomes Hereditary diseases Heterozygote Humans Inbreeding Male Models, Genetic Pedigree Phenotype Population studies Whole Exome Sequencing - statistics & numerical data |
| title | Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child |
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