The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling.
The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling.
复制标题
DOI：
10.1371/journal.pone.0290336
复制
发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.
登录
查看更多内容
DOI：
10.1002/ajmg.1320340406
发表时间：
1989-12-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
GREENBERG, DA
通讯作者：
GREENBERG, DA
影响因子：
1.9
作者：
SMITH, CAB
通讯作者：
SMITH, CAB
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
17.1
作者：
Minikel EV;Vallabh SM;Lek M;Estrada K;Samocha KE;Sathirapongsasuti JF;McLean CY;Tung JY;Yu LP;Gambetti P;Blevins J;Zhang S;Cohen Y;Chen W;Yamada M;Hamaguchi T;Sanjo N;Mizusawa H;Nakamura Y;Kitamoto T;Collins SJ;Boyd A;Will RG;Knight R;Ponto C;Zerr I;Kraus TF;Eigenbrod S;Giese A;Calero M;de Pedro-Cuesta J;Haïk S;Laplanche JL;Bouaziz-Amar E;Brandel JP;Capellari S;Parchi P;Poleggi A;Ladogana A;O'Donnell-Luria AH;Karczewski KJ;Marshall JL;Boehnke M;Laakso M;Mohlke KL;Kähler A;Chambert K;McCarroll S;Sullivan PF;Hultman CM;Purcell SM;Sklar P;van der Lee SJ;Rozemuller A;Jansen C;Hofman A;Kraaij R;van Rooij JG;Ikram MA;Uitterlinden AG;van Duijn CM;Exome Aggregation Consortium (ExAC);Daly MJ;MacArthur DG
通讯作者：
MacArthur DG
影响因子：
9.8
作者：
Thompson, D;Easton, DF;Goldgar, DE
通讯作者：
Goldgar, DE