Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene–Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong
Abstract
:1. Introduction
2. Patients and Methods
2.1. Patients and Ethics Statement
2.2. Whole Exome Sequencing (WES), Variant Calling, and Validation of Sequence Variants
2.3. Ovarian Stimulation, Fertilization, Embryo Culture, and Embryo Evaluation
2.4. Literature Review and Gene–Disease Clinical Validity Curation
3. Results
3.1. Clinical Description of Three Chinese Individuals with Oligoasthenozoospermia
3.2. Genetic Analysis Identifies Novel Heterozygous Loss-of-Function (LOF) SYCP2 Variants in the Patients
3.3. The Addition of Three Cases Upgrades the Strength of the Gene–Disease Relationship between SYCP2 and Autosomal Dominant Male Infertility to Strong
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Individual | Age at Diagnosis | Variant in SYCP2 | Exon | Clinical Diagnosis | Inheritance | Reference |
---|---|---|---|---|---|---|
M1686 | 29 | NM_014258.4:c.2022_2025del p.(Lys674Asnfs*8) | 24 | cryptozoospermia | Unknown | [8] |
M1581 | 27 | NM_014258.4:c.2793_2797del p.(Lys932Serfs*3) | 31 | cryptozoospermia | Maternal | [8] |
M1401 | 39 | NM_014258.4:c.3067_3071del p.(Lys1023Leufs*2) | 33 | azoospermia | Unknown | [8] |
Patient 1 | 30 | NM_014258.4:c.89dup p.(Leu30Phefs*4) | 4 | oligoasthenozoospermia | De novo | This study |
Patient 2 | 35 | NM_014258.4:c.946_947del p.(Ser316Ilefs*7) | 14 | oligoasthenozoospermia | Maternal | This study |
Patient 3 | 47 | NM_014258.4:c.4378_4379del p.(Arg1460Alafs*10) | 42 | severe | Unknown | This study |
oligoasthenozoospermia |
Genetic Evidence: Case-Level Data | |||||
---|---|---|---|---|---|
Evidence Type | Case Information | Suggested Point Upgrades | Points Given | References/Notes | |
Functional Data | De Novo | ||||
Variant Evidence: Autosomal Dominant | Predicted or proven null variant (default 1.5 points, scoring range 0–3 points per variant) | +0.5 | +0.5 | 9.5 | Six frameshift variants in SYCP2 resulting in premature termination codons have been found in men with infertility (see Table 1 with cases from this study and [8]). All the variants are predicted to cause nonsense-mediated decay of the transcripts as the premature termination codons reside greater than 50 bp upstream of the last exon–exon junction [20]. All cases were assigned the default of 1.5 points aside from patient 1 from this study, who received an additional 0.5 points due to the variant occurring de novo. |
Other variant type with some evidence of gene impact (default 0.1 points, scoring range 0–1.5 points per variant) | +0.4 | +0.4 | 0 | No evidence available | |
Segregation Evidence | Evidence of segregation in one or more families (scoring range 0–3 points) | 0 | No evidence available | ||
Genetic Evidence: Case-Control Data | |||||
Case-Control Study Type | Case-Control Quality Criteria | Suggested Points/Study | Points Given | References/Notes | |
Single Variant Analysis |
| 0–6 | 0 | No evidence available | |
Aggregate Variant Analysis | 0–6 | 0 | No evidence available | ||
Total Genetic Evidence Points (out of 12 Total Allowable Points) | 9.5 |
Experimental Evidence | |||||
---|---|---|---|---|---|
Evidence Category | Evidence Type | Suggested Points | Points Given | References/Notes | |
Default | Range | ||||
Function | Biochemical function | 0.5 | 0–2 | 0.5 | SYCP2 encodes synaptonemal complex protein 2, a component of the lateral element substructure of the synaptonemal complex (SC) [9,10]. The SC is essential for the meiotic process of synapsis, which is a critical step in spermatogenesis [22]. In Saccharomyces cerevisiae, mutant red1, the yeast functional homolog of SYCP2, fails to assemble the SC during meiotic prophase [24]. |
Protein interaction | 0.5 | 0–2 | 0.5 | The coiled-coil domain of mouse SYCP2 interacts with SYCP3 and TEX11, which have both been implicated in male infertility in humans [12,26,27,28]. | |
Expression | 0.5 | 0–2 | 0.5 | SYCP2 is expressed predominantly in testis tissue, where spermatogenesis occurs [23]. | |
Functional Alteration | Patient cells | 1 | 0–2 | 0.5 | Testicular biopsy histopathology from an individual with a heterozygous loss-of-function (LOF) variant in SYCP2 (participant M1401) shows a phenotype of meiotic arrest at the pachytene spermatocyte stage [8]. |
Non-patient cells | 0.5 | 0–1 | 0 | No evidence available | |
Models | Non-human model organism | 2 | 0–4 | 4 | Homozygous coiled-coil domain-deficient Sycp2 mice demonstrate male infertility and meiotic arrest (2 points) [12]. Testes from sycp2−/− zebrafish lack both spermatids and spermatozoa, resulting in the inability to fertilize eggs following natural mating with wild-type fish (2 points) [25]. |
Cell culture model | 1 | 0–2 | 0 | No evidence available | |
Rescue | Rescue in human | 2 | 0–4 | 0 | No evidence available |
Rescue in non-human model organism | 2 | 0–4 | 0 | No evidence available | |
Rescue in cell culture model | 1 | 0–2 | 0 | No evidence available | |
Rescue in patient cells | 1 | 0–2 | 0 | No evidence available | |
Total Experimental Evidence Points (out of 6 Total Allowable Points) | 6 |
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Li, J.; Schilit, S.L.P.; Liang, S.; Qin, N.; Teng, X.; Zhang, J. Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene–Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong. Genes 2024, 15, 1092. https://doi.org/10.3390/genes15081092
Li J, Schilit SLP, Liang S, Qin N, Teng X, Zhang J. Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene–Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong. Genes. 2024; 15(8):1092. https://doi.org/10.3390/genes15081092
Chicago/Turabian StyleLi, Jinli, Samantha L.P. Schilit, Shanshan Liang, Ningxin Qin, Xiaoming Teng, and Junyu Zhang. 2024. "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene–Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong" Genes 15, no. 8: 1092. https://doi.org/10.3390/genes15081092