• PMID: 31048812
• Gene Name: TDRD7
• Condition: Nonobstructive azoospermia
• Association: Associated
• Mutation: c.324_325insA (T110Nfs*30), c.688_689insA (p.Y230X)
• Population size: 698
• Population details: 698 (178 patients with azoospermia, 520 controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS
• Other associated phenotypes: Congenital cataract

Loss-of-function mutations in TDRD7 lead to a rare novel syndrome combining congenital cataract and nonobstructive azoospermia in humans

Tan YQ, Tu C, Meng L, Yuan S, Sjaarda C, Luo A, Du J, Li W, Gong F, Zhong C, Deng HX, Lu G, Liang P, Lin G.

PURPOSE: Comorbid familial nonobstructive azoospermia (NOA) and congenital cataract (CC) have not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose was to uncover novel human mutations and genes causing familial NOA and CC. METHODS: We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. RESULTS: Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and c.688_689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient's seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. CONCLUSION: We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance. FAU - Tan, Yue-Qiu AU - Tan YQ AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Tu, Chaofeng AU - Tu C AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Meng, Lanlan AU - Meng L AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Yuan, Shimin AU - Yuan S AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Sjaarda, Calvin AU - Sjaarda C AD - Department of Biological Sciences, Brock University, St. Catharines, Ontario, Canada. FAU - Luo, Aixiang AU - Luo A AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Du, Juan AU - Du J AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Li, Wen AU - Li W AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Gong, Fei AU - Gong F AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Zhong, Changgao AU - Zhong C AD - Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Deng, Han-Xiang AU - Deng HX AD - Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. FAU - Lu, Guangxiu AU - Lu G AD - Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. FAU - Liang, Ping AU - Liang P AD - Department of Biological Sciences, Brock University, St. Catharines, Ontario, Canada. pliang@brocku.ca.