Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease.
Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease.
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DOI：
10.1038/s41436-018-0281-4
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
DDD Study
中科院分区：
文献类型：
--
作者：
Wakeling MN;Laver TW;Wright CF;De Franco E;Stals KL;Patch AM;Hattersley AT;Flanagan SE;Ellard S;DDD Study
研究孟德尔病的人目前面临的最大挑战之一是从下一代测序测试产生的长长的列表中识别致病变异。我们研究了纯合性图谱用于识别可能包含致病变异的区域的预测能力。我们使用来自三个独立队列的179个纯合子致病变异体来研究纯合子图谱的预测能力。我们证明，在我们的队列中，纯合子致病变异体很可能出现在最大的纯合性区域之一：80%的致病变异体发现在样本中十个最大区域的纯合子区域。在端粒-lt；8%纯合性和>；3 Mb变异的患者中实现了最大的预测能力；这给出了曲线下面积(Auc)为0.735，导致92%的致病变异位于十个最大纯合子区域之一。这种预测能力可以用来确定基因发现研究中候选变异的优先顺序。在对纯合子变异进行分类时，候选变异所在纯合子区域的大小和等级也可以被认为是致病性的支持证据。
One of the greatest challenges currently facing those studying Mendelian disease is identifying the pathogenic variant from the long list produced by a next-generation sequencing test. We investigate the predictive ability of homozygosity mapping for identifying the regions likely to contain the causative variant. We use 179 homozygous pathogenic variants from three independent cohorts to investigate the predictive power of homozygosity mapping. We demonstrate that homozygous pathogenic variants in our cohorts are disproportionately likely to be found within one of the largest regions of homozygosity: 80% of pathogenic variants are found in a homozygous region that is in the ten largest regions in a sample. The maximal predictive power is achieved in patients with <8% homozygosity and variants >3 Mb from a telomere; this gives an area under the curve (AUC) of 0.735 and results in 92% of the causative variants being in one of the ten largest homozygous regions. This predictive power can be used to prioritize the list of candidate variants in gene discovery studies. When classifying a homozygous variant the size and rank of the region of homozygosity in which the candidate variant is located can also be considered as supporting evidence for pathogenicity.
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影响因子：
4.5
作者：
Mahmood K;Jung CH;Philip G;Georgeson P;Chung J;Pope BJ;Park DJ
通讯作者：
Park DJ
影响因子：
9.8
作者：
Pemberton, Trevor J.;Absher, Devin;Li, Jun Z.
通讯作者：
Li, Jun Z.
影响因子：
8.2
作者：
Ellard, S.;Allen, H. Lango;De Franco, E.;Flanagan, S. E.;Hysenaj, G.;Colclough, K.;Houghton, J. A. L.;Shepherd, M.;Hattersley, A. T.;Weedon, M. N.;Caswell, R.
通讯作者：
Caswell, R.
DOI：
10.1038/gim.2015.30
发表时间：
2015-05
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Richards S;Aziz N;Bale S;Bick D;Das S;Gastier-Foster J;Grody WW;Hegde M;Lyon E;Spector E;Voelkerding K;Rehm HL;ACMG Laboratory Quality Assurance Committee
通讯作者：
ACMG Laboratory Quality Assurance Committee
影响因子：
64.8
作者：
Deciphering Developmental Disorders Study
通讯作者：
Deciphering Developmental Disorders Study