Elizabeth E. Blue, Kristin J. Moore, Kari E. North, Tania A. Desrosiers, Suzan L. Carmichael, Janson J. White, Jessica X. Chong, Michael J. Bamshad, Mary M. Jenkins, Lynn M. Almli, Lawrence C. Brody, Sharon F. Freedman, Jennita Reefhuis, Paul A. Romitti, Gary M. Shaw, Martha Werler, Denise M. Kay, Marilyn L. Browne, Marcia L. Feldkamp, Richard H. Finnell, Wendy N. Nembhard, Faith Pangilinan, Andrew F. Olshan, the National Institutes of Health Intramural Sequencing Center, the University of Washington Center for Mendelian Genomics, the National Birth Defects Prevention Study
{"title":"外显子组测序在全国出生缺陷预防研究中发现了原发性先天性青光眼的新基因。","authors":"Elizabeth E. Blue, Kristin J. Moore, Kari E. North, Tania A. Desrosiers, Suzan L. Carmichael, Janson J. White, Jessica X. Chong, Michael J. Bamshad, Mary M. Jenkins, Lynn M. Almli, Lawrence C. Brody, Sharon F. Freedman, Jennita Reefhuis, Paul A. Romitti, Gary M. Shaw, Martha Werler, Denise M. Kay, Marilyn L. Browne, Marcia L. Feldkamp, Richard H. Finnell, Wendy N. Nembhard, Faith Pangilinan, Andrew F. Olshan, the National Institutes of Health Intramural Sequencing Center, the University of Washington Center for Mendelian Genomics, the National Birth Defects Prevention Study","doi":"10.1002/bdr2.2384","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, <i>CYP1B1</i>, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997–2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Among candidate variants, <i>CYP1B1</i> was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., <i>CRYBB2</i>, <i>RXRA</i>, <i>GLI2</i>).</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.</p>\n </section>\n </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":null,"pages":null},"PeriodicalIF":1.6000,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study\",\"authors\":\"Elizabeth E. Blue, Kristin J. Moore, Kari E. North, Tania A. Desrosiers, Suzan L. Carmichael, Janson J. White, Jessica X. Chong, Michael J. Bamshad, Mary M. Jenkins, Lynn M. Almli, Lawrence C. Brody, Sharon F. Freedman, Jennita Reefhuis, Paul A. Romitti, Gary M. Shaw, Martha Werler, Denise M. Kay, Marilyn L. Browne, Marcia L. Feldkamp, Richard H. Finnell, Wendy N. Nembhard, Faith Pangilinan, Andrew F. Olshan, the National Institutes of Health Intramural Sequencing Center, the University of Washington Center for Mendelian Genomics, the National Birth Defects Prevention Study\",\"doi\":\"10.1002/bdr2.2384\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, <i>CYP1B1</i>, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997–2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Among candidate variants, <i>CYP1B1</i> was most represented (five trios, 13.5%). 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Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study
Background
Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.
Methods
We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997–2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.
Results
Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2).
Conclusion
Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.
期刊介绍：
The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks.
Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.
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