• PMID: 32170493
• Gene Name: DNAAF6
• Condition: Primary ciliary dyskinesia (PCD) and male infertility
• Association: Associated
• Mutation: c.319_329del: p.R107fs, c.290G>T: p.G97V
• Population size: 442
• Population details: 2 families, 442 individuals (219 with isolated oligoasthenospermia and 223 fertile controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Novel DNAAF6 variants identified by whole-exome sequencing cause male infertility and primary ciliary dyskinesia

Wang Y, Tu C, Nie H, Meng L, Li D, Wang W, Zhang H, Lu G, Lin G, Tan YQ, Du J.

PURPOSE: To identify the genetic cause of patients with primary ciliary dyskinesia (PCD) and male infertility from two unrelated Han Chinese families. METHODS: We conducted whole-exome sequencing of three individuals with PCD and male infertility from two unrelated Chinese families, and performed a targeted look-up for DNAAF6 variants in our previously reported cohort of 442 individuals (219 with isolated oligoasthenospermia and 223 fertile controls). Ultrastructural and immunostaining analyses of patients' spermatozoa were performed. The pathogenicity of the variants was validated using patient's spermatozoa and HEK293T cells. Intracytoplasmic sperm injection (ICSI) treatment was conducted in two patients. RESULTS: We identified one novel hemizygous frameshift variant (NM_173494, c.319_329del: p.R107fs) of DNAAF6 gene (previously named PIH1D3) in family 1 and one novel hemizygous missense variant (c.290G>T: p.G97V) in family 2. No hemizygous deleterious variants in DNAAF6 were detected in the control cohort of 442 individuals. Ultrastructural and immunostaining analyses of patients' spermatozoa showed the absence of outer and inner dynein arms in sperm flagella. Both variants were proven to lead to DNAAF6 protein degradation in HEK293T cells. Both patients carrying DNAAF6 variants underwent one ICSI cycle and delivered one healthy child each. CONCLUSION: We identified novel DNAAF6 variants causing male infertility and PCD in Han Chinese patients. This finding extended the spectrum of variants in DNAAF6 and revealed new light on the impact of DNAAF6 variants in sperm flagella. FAU - Wang, Ying AU - Wang Y AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. FAU - Tu, Chaofeng AU - Tu C AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. FAU - Nie, Hongchuan AU - Nie H AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. FAU - Meng, Lanlan AU - Meng L AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. FAU - Li, Dongyan AU - Li D AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. FAU - Wang, Weili AU - Wang W AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. FAU - Zhang, Huan AU - Zhang H AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. FAU - Lu, Guangxiu AU - Lu G AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Lin, Ge AU - Lin G AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Tan, Yue-Qiu AU - Tan YQ AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. tanyueqiu@csu.edu.cn. AD - Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, 410078, Hunan, China. tanyueqiu@csu.edu.cn.