Diverse monogenic subforms of human spermatogenic failure

Autores da FMUP
Participantes de fora da FMUP
- Nagirnaja, L
- Lopes, A.
- Charng, WL
- Miller, B
- Stakaitis, R
- Golubickaite, I
- Stendahl, A
- Luan, TPC
- Friedrich, C
- Mahyari, E
- Fadial, E
- Kasak, L
- Vigh-Conrad, K
- Oud, MS
- Xavier, MJ
- Cheers, SR
- James, ER
- Guo, JT
- Jenkins, TG
- Riera-Escamilla, A
- Barros, A
- Goncalves, J
- Gurnett, CA
- Jorgensen, N
- Jezek, D
- Jungheim, ES
- Kliesch, S
- McLachlan, RI
- Omurtag, KR
- Pilatz, A
- Sandlow, J
- Smith, J
- Eisenberg, ML
- Hotaling, JM
- Jarvi, KA
- Punab, M
- Rajpert-De Meyts, E
- Carrell, DT
- Krausz, C
- Laan, M
- O'Bryan, MK
- Schlegel, PN
- Tuttelmann, F
- Veltman, JA
- Almstrup, K
- Aston, KI
- Conrad, DF
Unidades de investigação
Abstract
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human knockouts , and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.
© 2022. The Author(s).
Dados da publicação
- ISSN/ISSNe:
- 2041-1723, 2041-1723
- Tipo:
- Article
- Páginas:
- 7953-7953
- Link para outro recurso:
- www.scopus.com
Nature Communications Nature Publishing Group
Citações Recebidas na Web of Science: 17
Citações Recebidas na Scopus: 29
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- Não há documentos
Filiações
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Keywords
- COPY-NUMBER VARIATION; MULTIPLE MORPHOLOGICAL ABNORMALITIES; MALE-INFERTILITY; PIRNA BIOGENESIS; NUAGE FORMATION; VARIANTS; LOCALIZATION; GUIDELINES; MUTATIONS; DISCOVERY
Proyectos asociados
Rapid detection of aneuploidies in prenatal diagnostics
Investigador Principal: Filipa Abreu Gomes de Carvalho
Estudo Clínico Académico . 2021
Citar a publicação
Nagirnaja L,Lopes A,Charng WL,Miller B,Stakaitis R,Golubickaite I,Stendahl A,Luan TPC,Friedrich C,Mahyari E,Fadial E,Kasak L,Vigh K,Oud MS,Xavier MJ,Cheers SR,James ER,Guo JT,Jenkins TG,Riera A,Barros A,Carvalho F,Fernandes S,Goncalves J,Gurnett CA,Jorgensen N,Jezek D,Jungheim ES,Kliesch S,McLachlan RI,Omurtag KR,Pilatz A,Sandlow J,Smith J,Eisenberg ML,Hotaling JM,Jarvi KA,Punab M,Rajpert E,Carrell DT,Krausz C,Laan M,O'Bryan MK,Schlegel PN,Tuttelmann F,Veltman JA,Almstrup K,Aston KI,Conrad DF. Diverse monogenic subforms of human spermatogenic failure. Nat. Commun. 2022. 13. (1):p. 7953-7953. IF:16,600. (1).