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Article
Joris Veltman
Newcastle University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3218-8250
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De novo mutations (DNMs) are known to play a prominent role in many sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. We performed a trio-based exome-sequencing study in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.
Keywords
De novo mutations, male infertility, RBM5
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- SupplementaryNotes2GEMINIParticipatingAuthors.docx
Supplementary Notes 2
- Supplementaryfigures18.docx
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Supplementary Figures 1-8
- SupplementaryNotes1.docx
- SupplementaryTable1AllDNM.pdf
Supplementary Table 1
- SupplementaryTables25.docx
Supplementary Tables 2-5
- SupplementaryNotes2GEMINIParticipatingAuthors.docx
- SupplementaryNotesTables15.xlsx
Supplementary Notes Tables 1-5
- SupplementaryNotesTables15.xlsx
- SupplementaryNotes1.docx
Supplementary Notes 1
- SupplementaryTable1AllDNM.pdf
- SupplementaryTables25.docx
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Joris Veltman
Newcastle University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3218-8250
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 22 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
De novo mutations (DNMs) are known to play a prominent role in many sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. We performed a trio-based exome-sequencing study in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.
Figure 1
Figure 2
Figure 3
Figure 4
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