Evaluation of Risk Factors and a Gene Panel as a Tool for Unexplained Infertility Diagnosis by Next-Generation Sequencing
Abstract
1. Introduction
2. Materials and Methods
Research and Diagnostic Procedure Workflow
3. Results
3.1. Gene Panel Characteristics
3.2. Anthropometry and Sociodemographic Characteristics of Study Participants
4. Discussion
Recommendations for Further Research
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Appendix A
Gene Name | Loci | Inheritance | Phenotype |
---|---|---|---|
MTHFR—Methylenetetrahydrofolate Reductase | 1p36.22 | AR | Implantation, blood flow to the uterus, and fetal development |
FOLR1—Folate Receptor Alpha | 11q13.4 | AR | Neurodegeneration due to cerebral folate transport deficiency |
SERPINE1—endothelial plasminogen activator inhibitor-1 (PAI1) | 7q22.1 | AD, AR | Negatively regulates fibrinolysis and impairs the dissolution of clots |
TCN2—Transcobalamin II | 22q12.2 | AD | Affects vitamin B12 transport |
CTH—Cystathionine Gamma-Lyase | 1p31.1 | AR | Affects homocysteine metabolism, potentially impacting fertility due to altered folate levels and impaired embryo development |
SLC19A1—Solute Carrier Family 19 Member 1 | 21q22.3 | AR | Disrupts folate transport, affecting DNA synthesis |
NOS3—Nitric Oxide Synthase 3 | 7q36.1 | AR | Affects nitric oxide production, impacting ovarian function and vascular health |
CYP19A1—Synaptonemal Complex Protein 3 | Xq13 | X-linked | Affects estrogen synthesis |
ESR1—Estrogen Receptor 1 | 6q25.1 | AD | Affects estrogen receptor function |
LIF—Leukemia Inhibitory Factor | 22q12.1 | AR | Affects uterine receptivity, potentially leading to implantation failure |
HABP2—Hyaluronan Binding Protein 2 | 10q26.13 | AD | Impacts embryo implantation |
MLH3—MutL Homolog 3 | 14q24.3 | AR | Affects DNA repair |
TUBB8—Tubulin Beta 8 | 10q24.32 | AR | Impacts oocyte division |
ZP1—Zona Pellucida Glycoprotein 1 | 11p11.2 | AR | Affects oocyte fertilization |
PADI6—Peptidyl Arginine Deiminase 6 | 1p36.13 | AR | Affects oocyte quality |
TLE6—Transducin-Like Enhancer of Split 6 | 9q21.2 | AR | Impacts folliculogenesis |
F2—Coagulation Factor II (Thrombin) | 11p11.2 | AR | Coagulation (thrombosis risk) |
CFTR—Cystic Fibrosis Transmembrane Conductance Regulator | 7q31.2 | AR | Mucous viscosity |
CAPN10—Calpain 10 | 2q37.3 | AR | Insulin sensitivity |
AR—Androgen Receptor | Xq11-12 | X-linked recessive (AR) | Related to partial androgen insensitivity |
FSHR—Follicle Stimulating Hormone Receptor | 2q21 | AD | Follicle development |
LHCGR—Luteinizing Hormone/Chorionic Gonadotropin Receptor | 2p21 | AD | Ovarian hormone response |
ACE—Angiotensin I Converting Enzyme | 17q23.3 | AD | Blood pressure regulation |
SOD2—Superoxide Dismutase 2 | 6q25.3 | AR | Oxidative stress regulation |
RNLS—Renalase, FAD-Dependent Amine Oxidase | 10q23.33 | AD | Renalase enzyme |
VDR—Vitamin D Receptor | 12q13.11 | AD | Vitamin D receptor function |
PALT2—Patatin Like Phospholipase Domain Containing 2) | 6p21.1 | AR | Oocyte development |
Appendix B
Gene Name | Loci | Inheritance | Phenotype |
---|---|---|---|
CATSPER1—cation channel sperm associated 2 | 11q13.1 | AR | Asthenozoospermia |
POLG—DNA Polymerase Gamma | 15q25.1 | AR/AD | Sperm quality and motility (linked to mitochondrial disorders). |
RPL23A—Ribosomal Protein L23a | 6p21.1 | AD | Spermatogenesis |
RPL4—Ribosomal Protein L4 | 15q22.2 | AD | Spermatogenesis |
RPS27A—Ribosomal Protein S27a | 19q13.2 | AD | Spermatogenesis |
RPS3—Ribosomal Protein S3 | 9q34.11 | AD | Spermatogenesis |
RPS8—Ribosomal Protein S3Ribosomal Protein S8 | 1p34.2 | AD | Spermatogenesis |
TOMM7—Translocase of Outer Mitochondrial Membrane 7 | 19p13.2 | AR | Spermatogenesis |
MTHFR—Methylenetetrahydrofolate Reductase | 1p36.22 | AR | Affects sperm DNA integrity through DNA methylation, leading to an increased frequency of early spontaneous miscarriages |
APLF—Aprataxin and PNKP Like Factor | 4q35.1 | AR | DNA damage repair |
CYB5R4—Cytochrome B5 Reductase 4 | 1q21.1 | AR | Preserves the cell from the buildup of reactive oxygen species (ROS) |
ERCC4—ERCC Excision Repair 4, Endonuclease Catalytic Subunit | 16p13.12 | AR | Spermatogenesis, fertilization, and embryo development |
TNRFSF21—Tumor Necrosis Factor Receptor Superfamily Member 21 | 19p13.2 | AR | Promotes apoptosis, mediated by BAX, involved in the mitochondrial apoptotic process |
MORC1—MORC Family CW-Type Zinc Finger 1 | 3q13.32 | AR | Participates in apoptosis, involved in early spermatogenesis |
PIWIL1—Piwi Like RNA-Mediated Gene Silencing 1 | 12q24.33 | AR | Spontaneous regeneration of stem cells, inhibition of DNA replication |
ZFAND6—Zinc Finger AN1-Type Containing 6 | 2q37.3 | AR | Regulates TNF alpha-induced NF kappa-B activation and apoptosis |
DPY19L2—Dpy-19 Like 2 | 12q14.2 | AR | Expressed in the testes and is required for elongation of the sperm head and acrosome formation during spermatogenesis |
ADAM3A—Metallopeptidase domain 3A | Xq11.2 | AD | Participates in gamete fusion during fertilization |
NXF2—nuclear RNA export factor 2 | Xq22.1 | - | Spermatogenesis |
SIRPB1—Signal-Regulatory Protein Beta 1 | 20p13 | AD | Spermatogenesis |
FSHR—Follicle Stimulating Hormone Receptor | 2p21 | AD | Luteinizing hormone resistance and Leydig cell hypoplasia |
LHCGR—Luteinizing Hormone/Choriogonadotropin Receptor | 2p16.3 | AD | Testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphrod itism with Leydig cell hypoplasia |
AR—Androgen Receptor | Xq11-12 | X-linked recessive (AR) | Related to partial androgen insensitivity |
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Harmful habits
|
Nutrition
|
Low-frequency electromagnetic fields
|
Noise and psychological stress |
Thermal effects |
Pesticides |
Heavy metals |
Medications, anabolic steroids |
Chlorinated water |
Genes for Male UI | Genes for Female UI |
---|---|
MTHFR; FOLR1; TCN2; CTH; C19A1; SYCP3; CYP19A1; ESR1; LIF; HABP2; MLH3; TUBB8; ZP1; PADI6; TLE6; F2; CFTR; CAPN10; AR; FSHR; LHCGR; ACE; PAI-1; SOD2; RNLS; VDR; PALT2 | CATSPER1; POLG; RPL23A; RPL4; RPS27A; RPS3; RPS8; TOMM7; MTHFR; APLF; CYB5R4; ERCC4; TNRFSF21; MORC1; PIWIL1; ZFAND6; RBMY1F; DPY19L2; ADAM3A; NXF2; SIRPB1; FSHR; LHCGR; AR |
Case | Gene (Transcript Isoform) | SNP ID | Polyphen | Consequence | Clinical Relevance |
---|---|---|---|---|---|
1 | UGT2B7 | rs61361928 COSV100535388 COSV5944185 | Probably damaging | Missense variant | Likely benign, Drug response |
2 | CATSPER2 | rs11638719 | Possibly damaging | Missense variant, Transcript variant | Not reported in ClinVar |
Case | Gene (Transcript Isoform) | SNP ID | Polyphen | Consequence | Clinical Relevance |
---|---|---|---|---|---|
1 | CAPN10 | rs201157354 | Probably damaging | Missense variant | Likely benign |
2 | MLH3 | rs28756986 CM013005 COSV53156471 | Probably damaging | Missense variant | Benign/likely benign |
3 | HABP2 | rs7080536 CM032937 COSV63490531 | Probably damaging | Missense variant | Risk factor/benign |
4 | GDF9 | rs61754582 CM066833 | Probably damaging | Missense variant | Likely benign |
5 | SLC19A1 | rs578206452 COSV60589312 | Probably damaging | Missense variant | Likely benign |
6 | IRS1 | rs41265094 CM942133 COSV99043455 | Probably damaging | Missense variant | Likely benign |
Variable | Categories | Cases (n = 10), N% | Control (n = 34), N% | p Value |
---|---|---|---|---|
Age group | 18–30 31–35 36–40 >41 | 2 (20) 7 (70) 1 (10) 0 (0) | 20 (58.8) 10 (29.4) 4 (11.8) 0 (0) | 0.582 |
BMI (kg/m2) 1 | <18.5 18.5–25 25–30 >30 | 0 (0) 9 (90) 1 (10) 0 (0) | 1 (2.9) 21 (61.8) 10 (29.4) 2 (5.9) | 0.574 |
Education | Primary High school Higher school University University degree | 0 (0) 2 (20) 0 (0) 0 (0) 8 (80) | 2 (5.9) 8 (23.5) 8 (29.4) 6 (17.6) 10 (23.5) | 0.439 |
Sauna | Everyday Few times per week Few times per month Rarely Never | 0 (0) 0 (0) 0 (0) 7 (70) 3 (30) | 0 (0) 0 (0) 2 (5.9) 11 (32.4) 21 (61.8) | 0.476 |
Fast food | Everyday Few times per week Few times per month Rarely Never | 0 (0) 1 (10) 3 (30) 6 (60) 0 (0) | 0 (0) 6 (17.6) 12 (35.3) 11 (32.4) 5 (14.7) | 1.389 |
Preservatives in food | Everyday Few times per week Few times per month Rarely Never | 3 (30) 6 (60) 1 (10) 0 (0) 0 (0) | 6 (17.6) 16 (47.1) 6 (17.6) 4 (11.8) 2 (5.9) | 1.389 |
Laptop position | On the knees On the table Not using | 2 (20) 5 (50) 3 (30) | 0 (0) 30 (88.2) 4 (11.8) | 2.500 |
Microwave | Everyday Few times per week Few times per month Rarely Never | 0 (0) 2 (20) 3 (30) 5 (50) 0 (0) | 3 (8.8) 10 (29.4) 5 (14.7) 3 (8.8) 13 (38.2) | 4.044 |
Anabolic steroids | Yes No | 0 (0) 10 (100) | 0 (0) 34 (100) | 1.533 |
Pharmaceuticals | Yes No | 4 (40) 6 (60) | 2 (5.9) 32 (94.1) | 2.500 |
Physical activity | Everyday Few times per week Few times per month Rarely | 1 (10) 2 (20) 4 (40) 3 (30) | 5 (14.7) 8 (23.5) 5 (14.7) 16 (47.1) | 3.75 |
Pesticides | Yes No | 0 (0) 10 (100) | 0 (0) 34 (100) | 1.533 |
Smoking | Everyday Few times per week Few times per month Rarely Never | 2 (20) 0 (0) 3 (30) 0 (0) 5 (50) | 0 (0) 0 (0) 0 (0) 3 (8.8) 31 (91.2) | 3.50 |
Alcohol consumption | Everyday Few times per week Few times per month Rarely Never | 0 (0) 4 (40) 3 (30) 1 (10) 2 (20) | 0 (0) 3 (8.8) 2 (5.9) 12 (35.3) 17 (50) | 1.250 |
Stress level | Low Able to manage stress Level is alarming High | 1 (10) 8 (80) 1 (10) 0 (0) | 1 (2.9) 30 (88.2) 3 (8.8) 0 (0) | 4.732 |
Variable | Categories | Cases (n = 10), N% | Control (n = 34), N% | p Value |
---|---|---|---|---|
Age group | 18–30 31–35 36–40 >41 | 3 (30) 6 (60) 1 (10) 0 (0) | 14 (41.2) 10 (29.4) 8 (23.5) 2 (5.9) | 4.732 |
BMI (kg/m2) 1 | <18.5 18.5–25 25–30 >30 | 0 (0) 4 (40) 4 (40) 2 (20) | 0 (0) 17 (50) 12 (35.3) 5 (14.7) | 1.702 |
Education | Primary High school Higher school University University degree | 0 (0) 1 (10) 0 (0) 0 (0) 9 (90) | 1 (2.9) 9 (26.5 7 (20.6) 4 (11.8) 13 (38.2) | 2.403 |
Sauna | Everyday Few times per week Few times per month Rarely Never | 0 (0) 0 (0) 1 (10) 7 (70) 2 (20) | 0 (0) 0 (0) 4 (11.8) 18 (52.3) 12 (35.3) | 1.305 |
Fast food | Everyday Few times per week Few times per month Rarely Never | 1 (10) 2 (20) 4 (40) 3 (30) 0 (0) | 2 (5.9) 6 (17.6) 12 (17.6) 11 (32.4) 3 (8.8) | 1.043 |
Preservatives in food | Everyday Few times per week Few times per month Rarely Never | 3 (33.3) 5 (56.6) 1 (11.1) 0 (0) 0 (0) | 9 (18.8) 19 (39.6) 10 (20.8) 6 (12.5) 4 (8.3) | 1.204 |
Laptop position | On the knees On the table Not using | 2 (20) 8 (80) 0 (0) | 3 (8.8) 31 (91.2) 0 (0) | 1.043 |
Microwave | Everyday Few times per week Few times per month Rarely Never | 1 (11.1) 3 (33.3) 0 (0) 0 (0) 5 (55.6) | 4 (11.8) 9 (26.5) 6 (17.6) 5 (14.7) 10 (29.4) | 1.643 |
Anabolic steroids | Yes No | 0 (0) 10 (100) | 0 (0) 34 (100) | 1.533 |
Pharmaceuticals | Yes No | 3 (30) 7 (70) | 2 (5.9) 32 (94.1) | 1.435 |
Physical activity | Everyday Few times per week Few times per month Rarely | 2 (20) 2 (20) 3 (30) 3 (30) | 5 (10.4) 10 (20.8) 6 (17.6) 13 (38.2) | 1.643 |
Pesticides | Yes No | 0 (0) 10 (100) | 0 (0) 34 (100) | 1.533 |
Smoking | Everyday Few times per week Few times per month Rarely Never | 3 (30) 0 (0) 0 (0) 1 (10) 6 (60) | 8 (23.5) 3 (8.8) 1 (2.9) 2 (5.9) 20 (58.8) | 1.653 |
Alcohol consumption | Everyday Few times per week Few times per month Rarely Never | 0 (0) 1 (10) 6 (60) 2 (20) 1 (10) | 7 (21.2) 2 (6.1) 2 (6.1) 0 (0) 22 (66.7) | 1.534 |
Stress level | Low Able to manage stress Level is alarming High | 0 (0) 8 (80) 2 (20) 0 (0) | 1 (2.9) 31 (91.2) 2 (5.9) 0 (0) | 1.632 |
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Jašinskienė, E.; Sniečkutė, I.; Galminas, I.; Žemaitis, L.; Simutis, M.; Čaplinskienė, M. Evaluation of Risk Factors and a Gene Panel as a Tool for Unexplained Infertility Diagnosis by Next-Generation Sequencing. Medicina 2025, 61, 271. https://doi.org/10.3390/medicina61020271
Jašinskienė E, Sniečkutė I, Galminas I, Žemaitis L, Simutis M, Čaplinskienė M. Evaluation of Risk Factors and a Gene Panel as a Tool for Unexplained Infertility Diagnosis by Next-Generation Sequencing. Medicina. 2025; 61(2):271. https://doi.org/10.3390/medicina61020271
Chicago/Turabian StyleJašinskienė, Eglė, Ieva Sniečkutė, Ignas Galminas, Lukas Žemaitis, Mantas Simutis, and Marija Čaplinskienė. 2025. "Evaluation of Risk Factors and a Gene Panel as a Tool for Unexplained Infertility Diagnosis by Next-Generation Sequencing" Medicina 61, no. 2: 271. https://doi.org/10.3390/medicina61020271
APA StyleJašinskienė, E., Sniečkutė, I., Galminas, I., Žemaitis, L., Simutis, M., & Čaplinskienė, M. (2025). Evaluation of Risk Factors and a Gene Panel as a Tool for Unexplained Infertility Diagnosis by Next-Generation Sequencing. Medicina, 61(2), 271. https://doi.org/10.3390/medicina61020271