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Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders
- Source :
- Human Reproduction, 36, 9, pp. 2597-2611, Human Reproduction, 36, 2597-2611, Human Reproduction (Oxford, England)
- Publication Year :
- 2021
-
Abstract
- STUDY QUESTION What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders? SUMMARY ANSWER We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 10 out of 21 patients (48%) and variants in novel candidate genes in seven additional patients (33%). WHAT IS KNOWN ALREADY Severe sperm motility disorders are a form of male infertility characterised by immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum that do not affect viability. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 22 genes. STUDY DESIGN, SIZE, DURATION We performed exome sequencing in 21 patients with severe sperm motility disorders from two different clinics. PARTICIPANTS/MATERIALS, SETTING, METHOD Two groups of infertile men, one from Argentina (n = 9) and one from Australia (n = 12), with clinically defined severe sperm motility disorders (motility MAIN RESULTS AND ROLE OF CHANCE In 10 of 21 patients (48%), we identified pathogenic variants in known sperm assembly genes: CFAP43 (3 patients); CFAP44 (2 patients), CFAP58 (1 patient), QRICH2 (2 patients), DNAH1 (1 patient) and DNAH6 (1 patient). The diagnostic rate did not differ markedly between the Argentinian and the Australian cohort (55% and 42%, respectively). Furthermore, we identified patients with variants in the novel human candidate sperm motility genes: DNAH12, DRC1, MDC1, PACRG, SSPL2C and TPTE2. One patient presented with variants in four candidate genes and it remains unclear which variants were responsible for the severe sperm motility defect in this patient. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION In this study, we described patients with either a homozygous or two heterozygous candidate pathogenic variants in genes linked to sperm motility disorders. Due to unavailability of parental DNA, we have not assessed the frequency of de novo or maternally inherited dominant variants and could not determine the parental origin of the mutations to establish in all cases that the mutations are present on both alleles. WIDER IMPLICATIONS OF THE FINDINGS Our results confirm the likely causal role of variants in six known genes for sperm motility and we demonstrate that exome sequencing is an effective method to diagnose patients with severe sperm motility disorders (10/21 diagnosed; 48%). Furthermore, our analysis revealed six novel candidate genes for severe sperm motility disorders. Genome-wide sequencing of additional patient cohorts and re-analysis of exome data of currently unsolved cases may reveal additional variants in these novel candidate genes. STUDY FUNDING/COMPETING INTEREST(S) This project was supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., J.A.V. and R.I.M.L., The Netherlands Organisation for Scientific Research (918-15-667) to J.A.V., the Royal Society and Wolfson Foundation (WM160091) to J.A.V., as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. and Grants from the National Research Council of Argentina (PIP 0900 and 4584) and ANPCyT (PICT 9591) to H.E.C. and a UUKi Rutherford Fund Fellowship awarded to B.J.H.
- Subjects :
- Male
Candidate gene
candidate novel genes
sperm motility disorders
Bioinformatics
Asthenozoospermia
dysplasia of the fibrous sheath
male infertility
whole exome sequencing
Male infertility
03 medical and health sciences
0302 clinical medicine
Exome Sequencing
medicine
Humans
Exome
multiple morphological abnormalities of the sperm flagella
Infertility, Male
Sperm motility
Exome sequencing
asthenozoospermia
030304 developmental biology
0303 health sciences
030219 obstetrics & reproductive medicine
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
Sperm flagellum
business.industry
Rehabilitation
Other Research Radboud Institute for Health Sciences [Radboudumc 0]
Australia
Obstetrics and Gynecology
Original Articles
Reproductive Genetics
medicine.disease
AcademicSubjects/MED00905
Spermatozoa
Sperm
Reproductive Medicine
Sperm Tail
Sperm Motility
business
Subjects
Details
- ISSN :
- 02681161
- Database :
- OpenAIRE
- Journal :
- Human Reproduction, 36, 9, pp. 2597-2611, Human Reproduction, 36, 2597-2611, Human Reproduction (Oxford, England)
- Accession number :
- edsair.doi.dedup.....0724f92a98cae5f9743f6137ce611657