Diverse monogenic subforms of human spermatogenic failure

Data de publicação: Data Ahead of Print:

Autores da FMUP

  • Filipa Abreu Gomes De Carvalho

    Autor

  • Susana Maria Gouveia Fernandes

    Autor

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

Nature Communications  Nature Publishing Group

Tipo:
Article
Páginas:
7953-7953
Link para outro recurso:
www.scopus.com

Citações Recebidas na Web of Science: 17

Citações Recebidas na Scopus: 29

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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

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