Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men
Por:
Krausz, C, Riera-Escamilla, A, Moreno-Mendoza, D, Holleman, K, Cioppi, F, Algaba, F, Pybus, M, Friedrich, C, Wyrwoll, MJ, Casamonti, E, Pietroforte, S, Nagirnaja, L, Lopes, AM, Kliesch, S, Pilatz, A, Carrell, DT, Conrad, DF, Ars, E, Ruiz-Castane, E, Aston, KI, Baarends, WM, Tuttelmann, F
Publicada:
1 dic 2020
Ahead of Print:
1 ago 2020
Resumen:
Purpose Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Methods Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). Results We found strong evidence for five novel genes likely responsible for MA (ADAD2,TERB1,SHOC1,MSH4, andRAD21L1), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, nine patients carried pathogenic variants in seven previously reported genes-TEX14,DMRT1,TEX11,SYCE1,MEIOB,MEI1, andSTAG3-allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role. Conclusion Our findings contribute substantially to the development of a pre-testicular sperm extraction (TESE) prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between nonobstructive azoospermia (NOA) and cancer predisposition, and between NOA and premature ovarian failure.
Filiaciones:
Krausz, C:
Univ Florence, Dept Biomed Expt & Clin Sci Mario Serio, Florence, Italy
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Androl Dept, Barcelona, Catalonia, Spain
Riera-Escamilla, A:
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Androl Dept, Barcelona, Catalonia, Spain
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Mol Biol Lab, Barcelona, Catalonia, Spain
Moreno-Mendoza, D:
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Androl Dept, Barcelona, Catalonia, Spain
Holleman, K:
Erasmus MC Univ Med Ctr, Dept Dev Biol, Rotterdam, Netherlands
Cioppi, F:
Univ Florence, Dept Biomed Expt & Clin Sci Mario Serio, Florence, Italy
Algaba, F:
Univ Autonoma Barcelona, Fundacio Puigvert, Pathol Sect, Barcelona, Catalonia, Spain
Pybus, M:
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Mol Biol Lab, Barcelona, Catalonia, Spain
Friedrich, C:
Univ Munster, Inst Human Genet, Munster, Germany
Wyrwoll, MJ:
Univ Munster, Inst Human Genet, Munster, Germany
Casamonti, E:
Univ Florence, Dept Biomed Expt & Clin Sci Mario Serio, Florence, Italy
Pietroforte, S:
Univ Florence, Dept Biomed Expt & Clin Sci Mario Serio, Florence, Italy
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Mol Biol Lab, Barcelona, Catalonia, Spain
Nagirnaja, L:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Portland, OR 97201 USA
Lopes, AM:
Univ Porto, Inst Patol & Imunol Mol, Portugal IPATIMUP, Porto, Portugal
Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal
Kliesch, S:
Univ Hosp Munster, Ctr Reprod Med & Androl, Dept Clin & Surg Androl, Munster, Germany
Pilatz, A:
Justus Liebig Univ, Clin Urol Pediat Urol & Androl, Giessen, Germany
Carrell, DT:
Univ Utah, Sch Med, Dept Surg, Div Urol,Androl Lab, Salt Lake City, UT USA
Univ Utah, Sch Med, Dept Surg, Div Urol,IVF Lab, Salt Lake City, UT USA
Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA
Conrad, DF:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Portland, OR 97201 USA
Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA
Ars, E:
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Mol Biol Lab, Barcelona, Catalonia, Spain
Ruiz-Castane, E:
Univ Autonoma Barcelona, Inst Invest Biomed St Pau IIB St Pau, Fundacio Puigvert, Androl Dept, Barcelona, Catalonia, Spain
Aston, KI:
Univ Utah, Sch Med, Dept Surg, Div Urol,Androl Lab, Salt Lake City, UT USA
Univ Utah, Sch Med, Dept Surg, Div Urol,IVF Lab, Salt Lake City, UT USA
Baarends, WM:
Erasmus MC Univ Med Ctr, Dept Dev Biol, Rotterdam, Netherlands
Tuttelmann, F:
Univ Munster, Inst Human Genet, Munster, Germany
Green Accepted
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