Wei Zheng1, Huiling Hu2, Shuoping Zhang1, Xilin Xu2, Yong Gao3, Fei Gong1,2, Guangxiu Lu1,2, Ge Lin4,5. 1. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, 410008, China. 2. Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, 410008, China. 3. Wuhan BGI Clinical Laboratory Co., Ltd., Wuhan, 430075, China. 4. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, 410008, China. linggf@hotmail.com. 5. Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, 410008, China. linggf@hotmail.com.
Abstract
PURPOSE: TUBB8 is a gene that is frequently analysed in the genetic diagnosis of female infertility; 102 variants of this gene have been identified. However, the evaluation of its pathogenicity and the resulting phenotypes vary. Here, we aimed to identify novel TUBB8 variants as well as to summarize the reported variants and phenotypes in order for them to be included in genetic counselling analyses. METHODS: We performed whole exome sequencing to screen for candidate variants in 100 infertile female subjects and 100 controls who were able to conceive naturally. All variants were confirmed by Sanger sequencing. The effects of the variants in oocytes/arrested embryos were assessed by morphological observations, polar body biopsies, and chromosome analysis. A molecular modelling analysis was used to evaluate the possible effects of variants on protein secondary structure. RESULTS: We identified 29 TUBB8 variants, of which 20 were novel and five were maternally inherited. We identified three of a total of six recurrent variants that were specific for complete cleavage failure. Moreover, we obtained evidence that TUBB8 variants with large polar bodies had chromosome segregation errors. CONCLUSIONS: Our study expands the spectrum of TUBB8 variants, particularly for embryonic arrest. Together with the extant knowledge of TUBB8 variants, this study provides a foundation for the genetic counselling of female infertility.
PURPOSE: TUBB8 is a gene that is frequently analysed in the genetic diagnosis of female infertility; 102 variants of this gene have been identified. However, the evaluation of its pathogenicity and the resulting phenotypes vary. Here, we aimed to identify novel TUBB8 variants as well as to summarize the reported variants and phenotypes in order for them to be included in genetic counselling analyses. METHODS: We performed whole exome sequencing to screen for candidate variants in 100 infertile female subjects and 100 controls who were able to conceive naturally. All variants were confirmed by Sanger sequencing. The effects of the variants in oocytes/arrested embryos were assessed by morphological observations, polar body biopsies, and chromosome analysis. A molecular modelling analysis was used to evaluate the possible effects of variants on protein secondary structure. RESULTS: We identified 29 TUBB8 variants, of which 20 were novel and five were maternally inherited. We identified three of a total of six recurrent variants that were specific for complete cleavage failure. Moreover, we obtained evidence that TUBB8 variants with large polar bodies had chromosome segregation errors. CONCLUSIONS: Our study expands the spectrum of TUBB8 variants, particularly for embryonic arrest. Together with the extant knowledge of TUBB8 variants, this study provides a foundation for the genetic counselling of female infertility.
Authors: María C Lanuza-López; Sandra G Martínez-Garza; Jesús F Solórzano-Vázquez; Daniela Paz-Cervantes; Claudia González-Ortega; Israel Maldonado-Rosas; Gerardo Villegas-Moreno; Lina G Villar-Muñoz; Francisco A Arroyo-Méndez; Antonio M Gutiérrez-Gutiérrez; Raul E Piña-Aguilar Journal: Gynecol Endocrinol Date: 2020-02-17 Impact factor: 2.260
Authors: Maya N Mascarenhas; Seth R Flaxman; Ties Boerma; Sheryl Vanderpoel; Gretchen A Stevens Journal: PLoS Med Date: 2012-12-18 Impact factor: 11.069