Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.
Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.
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DOI：
10.1038/s41436-020-0897-z
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Gambin T;Liu Q;Karolak JA;Grochowski CM;Xie NG;Wu LR;Yan YH;Cao Y;Coban Akdemir ZH;Wilson TA;Jhangiani SN;Chen E;Eng CM;Muzny D;Posey JE;Yang Y;Zhang DY;Shaw C;Liu P;Lupski JR;Stankiewicz P
本研究的目的是评估外显子组测序（ES）数据库中低水平亲本嵌合体的规模。我们分析了来自贝勒-霍普金斯孟德尔基因组学中心（BHCMG）和贝勒遗传学中心（BG）的大约2000个家庭三重奏ES数据集。在受影响先证者中发现的明显新生单核苷酸变异（snv）中，我们选择了在先证者中变异等位基因分数（VAF）在30-70%之间，在父母一方中低于10%的罕见独特变异。在102个候选嵌合变异中，使用基于扩增子的NGS、微滴数字PCR或阻滞剂位移扩增验证，27个（26.4%）被确认为低（VAF在1-10%之间）或极低（VAF <1%）水平的嵌合。具有两个或两个以上交替读数的亲本样品的检测精度为63.6% （BHCMG）和43.6% （BG）。在9个被调查的个体中，我们观察到血液、唾液、成纤维细胞、口腔、头发和尿液样本中嵌合比率的变异性。我们的计算管道能够对真阳性和假阳性候选马赛克变体进行鲁棒区分，并有效检测ES样本中的低水平马赛克。我们证实，亲本样本中存在两个或更多的交替读数是低水平亲本体细胞嵌合的可靠预测因子。
The goal of this study was to assess the scale of low-level parental mosaicism in exome sequencing (ES) databases. We analyzed approximately 2000 family trio ES datasets from the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) and Baylor Genetics (BG). Among apparent de novo single nucleotide variants (SNVs) identified in the affected probands, we selected rare unique variants with variant allele fraction (VAF) between 30-70% in the probands and lower than 10% in one of the parents. Out of 102 candidate mosaic variants validated using amplicon-based NGS, droplet digital PCR, or blocker displacement amplification, 27 (26.4%) were confirmed to be low- (VAF between 1-10%) 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. 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.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
4
作者：
Ansari M;Poke G;Ferry Q;Williamson K;Aldridge R;Meynert AM;Bengani H;Chan CY;Kayserili H;Avci S;Hennekam RC;Lampe AK;Redeker E;Homfray T;Ross A;Falkenberg Smeland M;Mansour S;Parker MJ;Cook JA;Splitt M;Fisher RB;Fryer A;Magee AC;Wilkie A;Barnicoat A;Brady AF;Cooper NS;Mercer C;Deshpande C;Bennett CP;Pilz DT;Ruddy D;Cilliers D;Johnson DS;Josifova D;Rosser E;Thompson EM;Wakeling E;Kinning E;Stewart F;Flinter F;Girisha KM;Cox H;Firth HV;Kingston H;Wee JS;Hurst JA;Clayton-Smith J;Tolmie J;Vogt J;Tatton-Brown K;Chandler K;Prescott K;Wilson L;Behnam M;McEntagart M;Davidson R;Lynch SA;Sisodiya S;Mehta SG;McKee SA;Mohammed S;Holden S;Park SM;Holder SE;Harrison V;McConnell V;Lam WK;Green AJ;Donnai D;Bitner-Glindzicz M;Donnelly DE;Nellåker C;Taylor MS;FitzPatrick DR
通讯作者：
FitzPatrick DR
影响因子：
82.9
作者：
Breuss, Martin W.;Antaki, Danny;Gleeson, Joseph G.
通讯作者：
Gleeson, Joseph G.
影响因子：
12.3
作者：
Gambin, Tomasz;Jhangiani, Shalini N.;Boerwinkle, Eric
通讯作者：
Boerwinkle, Eric
影响因子：
4.1
作者：
Karolak, Justyna A.;Liu, Qian;Stankiewicz, Pawel
通讯作者：
Stankiewicz, Pawel