Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions

被引：32

作者：

Gambin, Tomasz ^{[1
,2
,3
]}

Liu, Qian ^{[1
]}

Karolak, Justyna A. ^{[1
,4
]}

Grochowski, Christopher M. ^{[1
]}

Xie, Nina G. ^{[5
]}

Wu, Lucia R. ^{[5
]}

Yan, Yan Helen ^{[6
]}

Cao, Ye ^{[1
,7
,8
]}

Akdemir, Zeynep H. Coban ^{[1
]}

Wilson, Theresa A. ^{[1
]}

Jhangiani, Shalini N. ^{[9
]}

Chen, Ed ^{[1
]}

Eng, Christine M. ^{[1
,7
]}

Muzny, Donna ^{[9
]}

Posey, Jennifer E. ^{[1
]}

Yang, Yaping ^{[1
,7
]}

Zhang, David Y. ^{[5
]}

Shaw, Chad ^{[1
,7
,10
]}

Liu, Pengfei ^{[1
,7
]}

Lupski, James R. ^{[1
,7
,11
,12
]}

Stankiewicz, Pawel ^{[1
,7
]}

机构：

[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Warsaw Univ Technol, Inst Comp Sci, Warsaw, Poland

[3] Inst Mother & Child Hlth, Dept Med Genet, Warsaw, Poland

[4] Poznan Univ Med Sci, Chair & Dept Genet & Pharmaceut Microbiol, Poznan, Poland

[5] Rice Univ, Dept Bioengn, Houston, TX USA

[6] NuProbe USA Inc, Houston, TX USA

[7] Baylor Genet, Houston, TX 77021 USA

[8] Chinese Univ Hong Kong, Dept Obstet & Gynecol, Hong Kong, Peoples R China

[9] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[10] Rice Univ, Dept Stat, Houston, TX 77251 USA

[11] Texas Childrens Hosp, Houston, TX 77030 USA

[12] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

来源：

GENETICS IN MEDICINE | 2020年 / 22卷 / 11期

关键词：

exome sequencing; parental somatic mosaicism; rare variants; Mendelian genomics; RECURRENCE RISK; MUTATIONS; VARIANTS; DISEASE; RATES; RARE;

D O I：

10.1038/s41436-020-0897-z

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose: The goal of this study was to assess the scale of low-level parental mosaicism in exome sequencing (ES) databases. Methods: We analyzed approximately 2000 family trio ES data sets from the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) and Baylor Genetics (BG). Among apparent de novo single-nucleotide variants identified in the affected probands, we selected rare unique variants with variant allele fraction (VAF) between 30% and 70% in the probands and lower than 10% in one of the parents. Results: Of 102 candidate mosaic variants validated using amplicon-based next-generation sequencing, droplet digital polymerase chain reaction, or blocker displacement amplification, 27 (26.4%) were confirmed to be low- (VAF between 1% and 10%) or very low (VAF <1%) level mosaic. Detection precision in parental samples with two or more alternate reads was 63.6% (BHCMG) and 43.6% (BG). In nine investigated individuals, we observed variability of mosaic ratios among blood, saliva, fibroblast, buccal, hair, and urine samples. Conclusion: Our computational pipeline enables robust discrimination between true and false positive candidate mosaic variants and efficient detection of low-level mosaicism in ES samples. We confirm that the presence of two or more alternate reads in the parental sample is a reliable predictor of low-level parental somatic mosaicism.

引用

页码：1768 / 1776

页数：9

共 39 条

[1] Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation [J].

Acuna-Hidalgo, Rocio ;

Bo, Tan ;

Kwint, Michael P. ;

van de Vorst, Maartje ;

Pinelli, Michele ;

Veltman, Joris A. ;

Hoischen, Alexander ;

Vissers, Lisenka E. L. M. ;

Gilissen, Christian .

AMERICAN JOURNAL OF HUMAN GENETICS, 2015, 97 (01) :67-74

[2] Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism [J].

Ansari, Morad ;

Poke, Gemma ;

Ferry, Quentin ;

Williamson, Kathleen ;

Aldridge, Roland ;

Meynert, Alison M. ;

Bengani, Hemant ;

Chan, Cheng Yee ;

Kayserili, Hulya ;

Avci, Sahin ;

Hennekam, Raoul C. M. ;

Lampe, Anne K. ;

Redeker, Egbert ;

Homfray, Tessa ;

Ross, Alison ;

Smeland, Marie Falkenberg ;

Mansour, Sahar ;

Parker, Michael J. ;

Cook, Jacqueline A. ;

Splitt, Miranda ;

Fisher, Richard B. ;

Fryer, Alan ;

Magee, Alex C. ;

Wilkie, Andrew ;

Barnicoat, Angela ;

Brady, Angela F. ;

Cooper, Nicola S. ;

Mercer, Catherine ;

Deshpande, Charu ;

Bennett, Christopher P. ;

Pilz, Daniela T. ;

Ruddy, Deborah ;

Cilliers, Deirdre ;

Johnson, Diana S. ;

Josifova, Dragana ;

Rosser, Elisabeth ;

Thompson, Elizabeth M. ;

Wakeling, Emma ;

Kinning, Esther ;

Stewart, Fiona ;

Flinter, Frances ;

Girisha, Katta M. ;

Cox, Helen ;

Firth, Helen V. ;

Kingston, Helen ;

Wee, Jamie S. ;

Hurst, Jane A. ;

Clayton-Smith, Jill ;

Tolmie, John ;

Vogt, Julie .

JOURNAL OF MEDICAL GENETICS, 2014, 51 (10) :659-668

[3] Recent segmental duplications in the human genome [J].

Bailey, JA ;

Gu, ZP ;

Clark, RA ;

Reinert, K ;

Samonte, RV ;

Schwartz, S ;

Adams, MD ;

Myers, EW ;

Li, PW ;

Eichler, EE .

SCIENCE, 2002, 297 (5583) :1003-1007

[4] Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females [J].

Bartnik, Magdalena ;

Derwinska, Katarzyna ;

Gos, Monika ;

Obersztyn, Ewa ;

Kolodziejska, Katarzyna E. ;

Erez, Ayelet ;

Szpecht-Potocka, Agnieszka ;

Fang, Ping ;

Terczynska, Iwona ;

Mierzewska, Hanna ;

Lohr, Naomi J. ;

Bellus, Gary A. ;

Reimschisel, Tyler ;

Bocian, Ewa ;

Mazurczak, Tadeusz ;

Cheung, Sau Wai ;

Stankiewicz, Pawel .

GENETICS IN MEDICINE, 2011, 13 (05) :447-452

[5] A genomic view of mosaicism and human disease [J].

Biesecker, Leslie G. ;

Spinner, Nancy B. .

NATURE REVIEWS GENETICS, 2013, 14 (05) :307-320

[6] Detection of Clinically Relevant Exonic Copy-Number Changes by Array CGH [J].

Boone, Philip M. ;

Bacino, Carlos A. ;

Shaw, Chad A. ;

Eng, Patricia A. ;

Hixson, Patricia M. ;

Pursley, Amber N. ;

Kang, Sung-Hae L. ;

Yang, Yaping ;

Wiszniewska, Joanna ;

Nowakowska, Beata A. ;

del Gaudio, Daniela ;

Xia, Zhilian ;

Simpson-Patel, Gayle ;

Immken, LaDonna L. ;

Gibson, James B. ;

Tsai, Anne C. -H. ;

Bowers, Jennifer A. ;

Reimschisel, Tyler E. ;

Schaaf, Christian P. ;

Potocki, Lorraine ;

Scaglia, Fernando ;

Gambin, Tomasz ;

Sykulski, Maciej ;

Bartnik, Magdalena ;

Derwinska, Katarzyna ;

Wisniowiecka-Kowalnik, Barbara ;

Lalani, Seema R. ;

Probst, Frank J. ;

Bi, Weimin ;

Beaudet, Arthur L. ;

Patel, Ankita ;

Lupski, James R. ;

Cheung, Sau Wai ;

Stankiewicz, Pawel .

HUMAN MUTATION, 2010, 31 (12) :1326-1342

[7] Autism risk in offspring can be assessed through quantification of male sperm mosaicism [J].

Breuss, Martin W. ;

Antaki, Danny ;

George, Renee D. ;

Kleiber, Morgan ;

James, Kiely N. ;

Ball, Laurel L. ;

Hong, Oanh ;

Mitra, Ileena ;

Yang, Xiaoxu ;

Wirth, Sara A. ;

Gu, Jing ;

Garcia, Camila A. B. ;

Gujral, Madhusudan ;

Brandler, William M. ;

Musaev, Damir ;

Nguyen, An ;

McEvoy-Venneri, Jennifer ;

Knox, Renatta ;

Sticca, Evan ;

Botello, Martha Cristina Cancino ;

Uribe Fenner, Javiera ;

Perez, Maria Carcel ;

Arranz, Maria ;

Moffitt, Andrea B. ;

Wang, Zihua ;

Hervas, Amaia ;

Devinsky, Orrin ;

Gymrek, Melissa ;

Sebat, Jonathan ;

Gleeson, Joseph G. .

NATURE MEDICINE, 2020, 26 (01) :143-+

[8] Somatic mosaicism: implications for disease and transmission genetics [J].

Campbell, Ian M. ;

Shaw, Chad A. ;

Stankiewicz, Pawel ;

Lupski, James R. .

TRENDS IN GENETICS, 2015, 31 (07) :382-392

[9] Parent of Origin, Mosaicism, and Recurrence Risk: Probabilistic Modeling Explains the Broken Symmetry of Transmission Genetics [J].

Campbell, Ian M. ;

Stewart, Jonathan R. ;

James, Regis A. ;

Lupski, James R. ;

Stankiewicz, Pawel ;

Olofsson, Peter ;

Shaw, Chad A. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2014, 95 (04) :345-359

[10] Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders [J].

Campbell, Ian M. ;

Yuan, Bo ;

Robberecht, Caroline ;

Pfundt, Rolph ;

Szafranski, Przemyslaw ;

McEntagart, Meriel E. ;

Nagamani, Sandesh C. S. ;

Erez, Ayelet ;

Bartnik, Magdalena ;

Wisniowiecka-Kowanik, Barbara ;

Plunkett, Katie S. ;

Pursley, Amber N. ;

Kang, Sung-Hae L. ;

Bi, Weimin ;

Lalani, Seema R. ;

Bacino, Carlos A. ;

Vast, Mala ;

Marks, Karen ;

Patton, Michael ;

Olofsson, Peter ;

Patel, Ankita ;

Veltman, Joris A. ;

Cheung, Sau Wai ;

Shaw, Chad A. ;

Vissers, Lisenka E. L. M. ;

Vermeesch, Joris R. ;

Lupski, James R. ;

Stankiewicz, Pawel .

AMERICAN JOURNAL OF HUMAN GENETICS, 2014, 95 (02) :173-182

← 1 2 3 4 →