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Mendelian Genomics

Since 2012, at Baylor College of Medicine (BCM), the Baylor-Johns Hopkins Center for Mendelian Genomics has initiated collaborations with nearly 275 investigators in 18 countries to identify novel disease genes in patients with hypothesized Mendelian disease and to describe the full extent of phenotypic expression of established Mendelian diseases (i.e. phenotypic expansion).

Towards this effort, the Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC) has generated more than 20 Tb of whole exome data for more than 300 phenotypes using its high-throughput multiplexed exome pipeline.

Whole exome sequencing (WES) is favored for the molecular analysis of Mendelian disorders because of its efficiency, cost effectiveness and the opportunity for novel gene/mutation discovery. Samples were multiplexed for both capture and sequencing, and full-length blocking oligos were employed for hybridization to enhance on target specificity. Using this format, ~10 Gb was generated for each sample to provide ~90% of the target bases at 20X coverage or greater. This pipeline, producing 3,000 capture libraries per month, is automated from library construction through annotated VCF generation in part using the ‘Mercury’ analysis pipeline. We have so far enrolled more than 4,000 subjects for the WES studies and completed sequencing for more than 2,500, resulting in the identification of disease causing mutations in 162 known and 91 novel genes.

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Related Publications

2015

COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis., Watkin, Levi B., Jessen Birthe, Wiszniewski Wojciech, Vece Timothy J., Jan Max, Sha Youbao, Thamsen Maike, Santos-Cortez Regie L. P., Lee Kwanghyuk, Gambin Tomasz, et al. , Nature genetics, 2015 Apr 20, (2015) Abstract
10.1038/ng.3279
Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing., Ritter, Deborah I., Haines Katherine, Cheung Hannah, Davis Caleb F., Lau Ching C., Berg Jonathan S., Brown Chester W., Thompson Patrick A., Gibbs Richard, Wheeler David A., et al. , Genetics in medicine : official journal of the American College of Medical Genetics, 2015 Jan 8, (2015) Abstract
10.1038/gim.2014.189
Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing., Ritter, Deborah I., Haines Katherine, Cheung Hannah, Davis Caleb F., Lau Ching C., Berg Jonathan S., Brown Chester W., Thompson Patrick A., Gibbs Richard, Wheeler David A., et al. , Genetics in medicine : official journal of the American College of Medical Genetics, 2015 Jan 8, (2015) Abstract
10.1038/nature14038
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities., Chong, Jessica X., Buckingham Kati J., Jhangiani Shalini N., Boehm Corinne, Sobreira Nara, Smith Joshua D., Harrell Tanya M., McMillin Margaret J., Wiszniewski Wojciech, Gambin Tomasz, et al. , American journal of human genetics, 2015 Jul 8, (2015) Abstract
10.1158/2159-8290.CD-12-0537
Homozygous loss-of-function mutations in SOHLH1 in patients with non-syndromic hypergonadotropic hypogonadism., Bayram, Yavuz, Gulsuner Suleyman, Guran Tulay, Abaci Ayhan, Yesil Gozde, Gulsuner Hilal Unal, Atay Zeynep, Pierce Sarah B., Gambin Tomasz, Lee Ming, et al. , The Journal of clinical endocrinology and metabolism, 2015 Mar 16, p.jc20151150, (2015) Abstract
10.1038/nature14038

2014

Mechanism, Prevalence, and More Severe Neuropathy Phenotype of the Charcot-Marie-Tooth Type 1A Triplication., Liu, Pengfei, Gelowani Violet, Zhang Feng, Drory Vivian E., Ben-Shachar Shay, Roney Erin, Medeiros Adam C., Moore Rebecca J., Divincenzo Christina, Burnette William B., et al. , American journal of human genetics, 2014 Mar 6, Volume 94, Issue 3, p.462-9, (2014) Abstract
10.1016/j.ajhg.2014.01.017
De Novo Truncating Mutations in AHDC1 in Individuals with Syndromic Expressive Language Delay, Hypotonia, and Sleep Apnea., Xia, Fan, Bainbridge Matthew N., Tan Tiong Yang, Wangler Michael F., Scheuerle Angela E., Zackai Elaine H., Harr Margaret H., Sutton Reid V., Nalam Roopa L., Zhu Wenmiao, et al. , American journal of human genetics, 2014 May 1, Volume 94, Issue 5, p.784-9, (2014) Abstract
10.1016/j.ajhg.2014.04.006
Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal., Sun, Deqiang, Luo Min, Jeong Mira, Rodriguez Benjamin, Xia Zheng, Hannah Rebecca, Wang Hui, Le Thuc, Faull Kym F., Chen Rui, et al. , Cell stem cell, 2014 May 1, Volume 14, Issue 5, p.673-88, (2014) Abstract
10.1016/j.stem.2014.03.002
Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing., Yang, Yaping, Muzny Donna M., Xia Fan, Niu Zhiyv, Person Richard, Ding Yan, Ward Patricia, Braxton Alicia, Wang Min, Buhay Christian, et al. , JAMA, 2014 Oct 18, (2014) Abstract
10.1001/jama.2014.14601
A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases., Yamamoto, Shinya, Jaiswal Manish, Charng Wu-Lin, Gambin Tomasz, Karaca Ender, Mirzaa Ghayda, Wiszniewski Wojciech, Sandoval Hector, Haelterman Nele A., Xiong Bo, et al. , Cell, 2014 Sep 25, Volume 159, Issue 1, p.200-14, (2014) Abstract
10.1016/j.cell.2014.09.002

2013

PhenoDB: a new web-based tool for the collection, storage, and analysis of phenotypic features., Hamosh, Ada, Sobreira Nara, Hoover-Fong Julie, Sutton Reid V., Boehm Corinne, Schiettecatte François, and Valle David , Human mutation, 2013 Apr, Volume 34, Issue 4, p.566-71, (2013) Abstract
10.1002/humu.22283
Mutations in KCTD1 cause scalp-ear-nipple syndrome., Marneros, Alexander G., Beck Anita E., Turner Emily H., McMillin Margaret J., Edwards Matthew J., Field Michael, de Macena Sobreira Nara Lygia, Perez Ana Beatriz A., Fortes Jose A. R., Lampe Anne K., et al. , American journal of human genetics, 2013 Apr 4, Volume 92, Issue 4, p.621-6, (2013) Abstract
10.1016/j.ajhg.2013.03.002
Whole-genome sequence-based analysis of high-density lipoprotein cholesterol., Morrison, Alanna C., Voorman Arend, Johnson Andrew D., Liu Xiaoming, Yu Jin, Li Alexander, Muzny Donna, Yu Fuli, Rice Kenneth, Zhu Chengsong, et al. , Nature genetics, 2013 Aug, Volume 45, Issue 8, p.899-901, (2013) Abstract
10.1016/j.annepidem.2008.07.004
ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry., Hjeij, Rim, Lindstrand Anna, Francis Richard, Zariwala Maimoona A., Liu Xiaoqin, Li You, Damerla Rama, Dougherty Gerard W., Abouhamed Marouan, Olbrich Heike, et al. , American journal of human genetics, 2013 Aug 8, Volume 93, Issue 2, p.357-67, (2013) Abstract
10.1016/j.ajhg.2013.06.009
TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities., Wiszniewski, Wojciech, Hunter Jill V., Hanchard Neil A., Willer Jason R., Shaw Chad, Tian Qi, Illner Anna, Wang Xueqing, Cheung Sau W., Patel Ankita, et al. , American journal of human genetics, 2013 Aug 8, Volume 93, Issue 2, p.197-210, (2013) Abstract
10.1016/j.ajhg.2013.07.017
Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome., Vatta, Matteo, Niu Zhiyv, Lupski James R., Putnam Philip, Spoonamore Katherine G., Fang Ping, Eng Christine M., and Willis Alecia S. , American journal of medical genetics. Part A, 2013 Dec, Volume 161A, Issue 12, p.3182-6, (2013) Abstract
10.1002/ajmg.a.36178
Dawn of ocular gene therapy: implications for molecular diagnosis in retinal disease., Zaneveld, Jacques, Wang Feng, Wang Xia, and Chen Rui , Science China. Life sciences, 2013 Feb, Volume 56, Issue 2, p.125-33, (2013) Abstract
10.1136/jmedgenet-2013-101558
Incidental copy-number variants identified by routine genome testing in a clinical population., Boone, Philip M., Soens Zachry T., Campbell Ian M., Stankiewicz Pawel, Cheung Sau Wai, Patel Ankita, Beaudet Arthur L., Plon Sharon E., Shaw Chad A., McGuire Amy L., et al. , Genetics in medicine : official journal of the American College of Medical Genetics, 2013 Jan, Volume 15, Issue 1, p.45-54, (2013) Abstract
10.1038/gim.2012.95
Integrated genomic characterization of endometrial carcinoma., Kandoth, Cyriac, Schultz Nikolaus, Cherniack Andrew D., Akbani Rehan, Liu Yuexin, Shen Hui, Robertson Gordon A., Pashtan Itai, Shen Ronglai, Benz Christopher C., et al. , Nature, 2013 May 2, Volume 497, Issue 7447, p.67-73, (2013) Abstract
10.1038/nature12113
Replicative mechanisms for CNV formation are error prone., Carvalho, Claudia M. B., Pehlivan Davut, Ramocki Melissa B., Fang Ping, Alleva Benjamin, Franco Luis M., Belmont John W., Hastings P. J., and Lupski James R. , Nature genetics, 2013 Nov, Volume 45, Issue 11, p.1319-26, (2013) Abstract
10.1038/ng.2768
Detection of clinically relevant copy number variants with whole-exome sequencing., de Ligt, Joep, Boone Philip M., Pfundt Rolph, Vissers Lisenka E. L. M., Richmond Todd, Geoghegan Joel, O'Moore Kathleen, de Leeuw Nicole, Shaw Christine, Brunner Han G., et al. , Human mutation, 2013 Oct, Volume 34, Issue 10, p.1439-48, (2013) Abstract
10.1002/humu.22387
Mutations in VRK1 Associated With Complex Motor and Sensory Axonal Neuropathy Plus Microcephaly., Gonzaga-Jauregui, Claudia, Lotze Timothy, Jamal Leila, Penney Samantha, Campbell Ian M., Pehlivan Davut, Hunter Jill V., Woodbury Suzanne L., Raymond Gerald, Adesina Adekunle M., et al. , JAMA neurology, 2013 Oct 14, (2013) Abstract
10.1001/jamaneurol.2013.4598
Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D., Okamoto, Yuji, Goksungur Meryem Tuba, Pehlivan Davut, Beck Christine R., Gonzaga-Jauregui Claudia, Muzny Donna M., Atik Mehmed M., Carvalho Claudia M. B., Matur Zeliha, Bayraktar Serife, et al. , Genetics in medicine : official journal of the American College of Medical Genetics, 2013 Oct 17, (2013) Abstract
10.1038/gim.2013.155
Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles., Boone, Philip M., Campbell Ian M., Baggett Brett C., Soens Zachry T., Rao Mitchell M., Hixson Patricia M., Patel Ankita, Bi Weimin, Cheung Sau Wai, Lalani Seema R., et al. , Genome research, 2013 Sep, Volume 23, Issue 9, p.1383-94, (2013) Abstract
10.1101/gr.156075.113

2012

10.1371/journal.pone.0031358
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