Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure

Riera-Escamilla, Antoni; Vockel, Matthias; Nagirnaja, Liina; Xavier, Miguel J; Carbonell, Albert; Moreno-Mendoza, Daniel; Pybus, Marc; Farnetani, Ginevra; Rosta, Viktória; Cioppi, Francesca; Friedrich, Corinna; Oud, Manon S; Heijden, Godfried W. van der; Soave, Armin; Diemer, Thorsten; Ars, Elisabet; Sánchez‐Curbelo, Josvany; Kliesch, Sabine; Ruíz-Castañé, Eduard; Azorı́n, Fernando; Veltman, Joris A.; Aston, Kenneth I.; Conrad, Donald F.; Tüttelmann, Frank; Krausz, Csilla

doi:10.1016/j.ajhg.2022.06.007

Cited by 16 publications

(19 citation statements)

References 60 publications

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“…With the increasing application of WES, the number of reported monogenic causes of human male infertility has strikingly increased within the last 5 years. Many of these studies, like the first large-scale analyses in the GEMINI cohort 25 , IMIGC X-chromosomal variants 36 , and trio-exomes 27 , aim to identify novel candidate genes and/or understand the biological pathways relevant to spermatogenesis. Still, even in large and clinically well characterized cohorts of NOA men, often only singular cases per gene are identified making it difficult to judge whether an identified gene is a valid disease gene or remains a candidate gene awaiting confirmation.…”

Section: Discussionmentioning

confidence: 99%

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia

et al. 2023

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Non-obstructive azoospermia, the absence of sperm in the ejaculate due to disturbed spermatogenesis, represents the most severe form of male infertility. De novo microdeletions of the Y-chromosomal AZFa region are one of few well-established genetic causes for NOA and are routinely analysed in the diagnostic workup of affected men. So far, it is unclear which of the three genes located in the AZFa chromosomal region is indispensible for germ cell maturation. Here we present four different likely pathogenic loss-of-function variants in the AZFa gene DDX3Y identified by analysing exome sequencing data of more than 1,600 infertile men. Three of the patients underwent testicular sperm extraction and revealed the typical AZFa testicular Sertoli cell-only phenotype. One of the variants was proven to be de novo. Consequently, DDX3Y represents the AZFa key spermatogenic factor and screening for variants in DDX3Y should be included in the diagnostic workflow.

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Section: Discussionmentioning

confidence: 99%

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia

et al. 2023

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“…The observed detection rate of possible causes of NOA in GEMINI (20%) remains a conservative estimate, as our approach did not consider genes exclusively involved in fetal gonad development, excluded genes with broad expression across the body, and did not address dominant or additive defects likely to contribute to the manifestation of NOA as well 47,48 . A more detailed analysis of X-linked genes is reported in a companion paper focusing exclusively on the X chromosome, using a different method of prioritization than described here 49 .…”

Section: Discussionmentioning

confidence: 99%

Diverse monogenic subforms of human spermatogenic failure

et al. 2022

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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.

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“…The vast majority of these men has unexplained NOA, while genetic causes have been identified in some of them. 6,32,37,[39][40][41][42] Exome sequencing in the GEMINI cohort was performed as previously described. 32 The Imperial cohort comprises 17 infertile men who are all azoospermic.…”

Section: Methodsmentioning

confidence: 99%

The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans

Wyrwoll

Gaasbeek²,

Golubickaitė³

et al. 2022

The American Journal of Human Genetics

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Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure

Cited by 16 publications

References 60 publications

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia

Diverse monogenic subforms of human spermatogenic failure

The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans

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