Female infertility arises from disruption of tightly integrated pathways that regulate the hypothalamic–pituitary–gonadal (HPG) axis, ovarian development and steroidogenesis, folliculogenesis and oocyte maturation, tubal and ciliary function, and broader disorders of sex development and reproductive tract anatomy. Germline variants in these pathways can lead to primary or secondary amenorrhea, anovulation, diminished ovarian response or premature ovarian insufficiency, luteal defects, implantation and early pregnancy failure, tubal factor infertility, and syndromic conditions where impaired fertility coexists with endocrine, skeletal, sensory, or systemic manifestations.
PreCheck Health Services’ Female Infertility & Reproductive Health Panel is a germline, targeted exome assay focused on genes with established or emerging roles in hypothalamic and pituitary regulation of gonadotropins, gonadal and sex-determining pathways, steroidogenesis and androgen/estrogen balance, meiosis and gametogenesis, fertilization biology, and ciliary/tubal function. The assay is intended for use on constitutional DNA (e.g., peripheral blood or saliva) and is not a somatic or tumor profiling test. By interrogating these loci, the panel supports molecular diagnosis across hypogonadotropic and hypergonadotropic hypogonadism, disorders of sex development, ovulatory dysfunction, cilia-related tubal factor infertility, and syndromic reproductive disorders, while also informing partner/testing strategies when clinically indicated.
This assay is designed for individuals assigned female at birth presenting with or at risk for:
● Primary infertility or subfertility of unclear etiology, including anovulation, irregular or absent menses, diminished ovarian response, or unexplained failure to conceive after standard endocrine, anatomic, and infectious evaluation
● Hypergonadotropic hypogonadism and suspected ovarian insufficiency, including primary ovarian insufficiency (POI), premature menopause, or impaired folliculogenesis potentially linked to meiotic or gonadal development gene defects
● Suspected disorders of gonadal development or sex determination (46,XX or 46,XY DSD phenotypes), such as atypical pubertal development, virilization, underdevelopment of ovarian structures, or conditions involving steroidogenesis pathway defects impacting estrogen/androgen balance
● Individuals with a personal or family history of hereditary reproductive disorders, including hypogonadotropic hypogonadism, ovarian insufficiency, ciliopathies, or carrier risk for conditions such as CFTR-related reproductive disease, where clarifying recurrence risk, partner risk, and reproductive planning strategies is clinically important
● Individuals undergoing assisted reproductive technology (ART) with recurrent fertilization failure, poor embryo development, or suspected gamete activation abnormalities, especially when couple-level genetic contributors may be relevant (e.g., PLCZ1-mediated oocyte activation defects)
This Female Infertility & Reproductive Health Panel targets germline (constitutional) variants in genes that regulate the hypothalamic–pituitary–gonadal axis, ovarian development and differentiation, steroidogenesis and sex-hormone signaling, oocyte maturation and meiotic integrity, ciliary and tubal function, and congenital or syndromic disorders that influence reproductive capability. The assay is designed for use on peripheral blood or saliva DNA and is not a somatic/tumor profiling test. Genes are organized into biologic and clinical pathways relevant to hypogonadotropic and hypergonadotropic hypogonadism, ovulatory dysfunction, primary ovarian insufficiency, disorders of sex development, tubal factor infertility associated with ciliary dysfunction, fertilization biology, and multisystem syndromes where impaired fertility is a significant feature.
1.HPG Axis, GnRH, and Gonadotropin Signaling
Genes that control GnRH synthesis and action, pituitary development, and gonadotropin production and signaling. Variants in these loci are associated with congenital hypogonadotropic hypogonadism (CHH), Kallmann spectrum, combined pituitary hormone deficiencies, and dysregulation of FSH/LH signaling, leading to anovulation, amenorrhea, and impaired follicular development.
● CHD7, FEZF1, FGF8, FGFR1, GNRH1, GNRHR, FSHB, FSHR, LHB, LHCGR, KISS1R, TAC3, TACR3, HESX1, LHX3, LHX4, NSMF, POU1F1, PROK2, PROKR2, PROP1, PCSK1, WDR11
2.Ovarian Development, Steroidogenesis, and Sex Determination
Genes in this category regulate early gonadal development, steroid hormone synthesis, and sex-determining pathways. Pathogenic variants can result in 46,XY or 46,XX disorders of sex development (DSD), gonadal dysgenesis, altered ovarian reserve or function, and abnormal androgen/estrogen balance that impacts ovulation and implantation.
● AIRE, BMP15, FOXL2, HOXA13, CYP11A1, CYP17A1, CYP19A1, CYP21A2, HSD3B2, HSD17B4, GDF9, STAR, POR, WT1, WNT4, NR5A1
3.Meiosis, Oocyte Maturation, Early Embryogenesis & Cohesin Function
Genes involved in meiotic recombination, synaptonemal complex/cohesin function, and genome integrity during gametogenesis. Germline variants are implicated in primary ovarian insufficiency, impaired oocyte maturation, recurrent pregnancy loss of gametic origin, and broader gonadal failure syndromes.
● FIGLA, KHDC3L, LARS2, MCM8, MCM9, MRPS22, MSH4, MSH5, NLRP5, PADI6, SOHLH1, SPATA22, STAG3, SYCE1, TLE6, TRIP13, RMND1
4.Mitochondrial & Metabolic Pathways Affecting Ovarian Function
These genes encode axonemal and peri-axonemal components, radial spoke and central apparatus proteins, and ciliary trafficking factors. While classically described in the context of sperm flagellar defects and male infertility, many of the same loci underlie primary ciliary dyskinesia (PCD) and related ciliopathies. In females, impaired motile cilia in the fallopian tubes and upper reproductive tract can contribute to tubal factor infertility, ectopic pregnancy risk, and subfertility.
● AARS2, ERAL1, HARS2, MRPS22, POLG, TWNK, PEX6, LMNA, LEP, LEPR, GALT
5.Disorders of Sex Development (DSD), Gonadal Dysgenesis & Steroid Hormone Imbalance
Variants affecting gonadal specification, sex differentiation, and steroid hormone action may lead to ambiguous genitalia, primary amenorrhea, ovarian dysgenesis, sex reversal conditions, and fertility impairment.
● WT1, WNT4, NR5A1, HOXA13, FOXL2, CYP11A1, CYP17A1, CYP19A1, HSD3B2
6.Fertilization Biology, Oocyte Activation & Early Embryo Competence
Genes required for oocyte activation, maternal-effect processes, and early embryonic genome regulation. Pathogenic variants may underlie recurrent fertilization failure, poor embryo development, or early ART failure..
● KHDC3L, NLRP5, PADI6, TLE6, FIGLA, SPATA22
Genes Analyzed 72 female fertility-related genes.
Technology Platform Illumina NGS (Hybrid-Capture Target Enrichment).
Coverage Metrics >98% bases at ≥20× read depth.
Variant Types Detected SNVs and small indels (≤20 bp) within coding exons ±10 bp intronic boundaries.
Reference Genome GRCh38/hg38.
Bioinformatics Pipeline SeqOne™, ACMG/AMP compliant.
Confirmatory Testing Sanger sequencing or orthogonal method as indicated.
Turnaround Time ~10 calendar days.
Quality Metrics Read quality ≥Q30; allelic balance ≥0.3; minimum coverage 20×.
1.Primary Female Infertility, Ovulatory Dysfunction, and Ovarian Failure
❖ Clarify the etiology of anovulation, irregular or absent menses, reduced ovarian reserve, or primary ovarian insufficiency (POI) in individuals whose standard evaluations (endocrine studies, pelvic ultrasound, AMH levels) are inconclusive
❖ Distinguish intrinsic ovarian or meiotic dysfunction from endocrine, metabolic,
❖ Support prognosis for natural conception versus the need for assisted reproductive technologies (ART), and inform expectations regarding treatment success rates and counseling for alternative family-building options
2.Hypogonadotropic and Hypogonadism, Pubertal Disorders, and Endocrine Evaluation
❖ Identify genetic causes of congenital hypogonadotropic hypogonadism (CHH), Kallmann syndrome, combined pituitary hormone deficiencies, and primary testicular failure in adolescents and adults with delayed or absent puberty, low testosterone, and abnormal gonadotropins
❖ Differentiate isolated reproductive axis defects from broader pituitary or syndromic endocrinopathies, guiding appropriate endocrine workup, imaging, and monitoring for associated hormonal deficiencies
❖ Inform individualized management plans, including timing and selection of hormone replacement, induction of puberty, and fertility-directed therapies (e.g., gonadotropin or GnRH therapy) where feasible
3.Disorders of Sex Development (DSD), Androgen Pathway Defects, and Genital Anomalies
❖ Define the molecular basis of 46, XY DSD, ambiguous or undervirilized genitalia, severe hypospadias, gonadal dysgenesis, and suspected androgen insensitivity or steroidogenic enzyme deficiencies
❖ Refine risk assessment for gonadal malignancy, inform decisions about sex assignment, timing and extent of genital or gonadal surgery, and long-term endocrine replacement strategies
❖ Support multidisciplinary DSD team management by providing a precise genetic diagnosis that can be integrated with endocrine, surgical, psychological, and ethical considerations across childhood and adulthood
4.Ciliary Dysfunction, Tubal Factor Infertility, and ART Outcomes
❖ Inform ART strategy (e.g., ICSI vs alternative approaches), counseling regarding the likelihood of fertilization success, and discussion of reproductive risks to offspring when pathogenic variants are transmitted through ART that bypasses natural selection
5.Syndromic Reproductive Disorders, Family Management, and Cascade Testing
❖ Recognize syndromic and multisystem conditions—such as Bardet–Biedl spectrum disorders, CHARGE-related hypogonadism, CFTR-related reproductive disease, and gonadal development gene defects—where infertility is part of a broader phenotype
❖ Provide actionable information for reproductive planning, including partner testing (e.g., CFTR), discussion of preimplantation or prenatal genetic testing, and assessment of couple-level reproductive risk
Female Infertility & Reproductive Health genetic testing provides clinically actionable information across reproductive endocrinology, gynecology, medical genetics, fertility medicine, primary care, and assisted reproductive technology (ART) programs. Results directly influence diagnostic clarification, management planning, treatment selection, and family-building strategies.
Risk Stratification and Diagnostic Clarification Identify pathogenic or likely pathogenic variants underlying anovulation, diminished ovarian reserve, primary ovarian insufficiency, congenital hypogonadotropic hypogonadism, steroidogenesis pathway defects, disorders of sex development, and ciliary or tubal causes of infertility. Distinguish intrinsic ovarian or oocyte-related dysfunction from endocrine, anatomic, or acquired contributors. Refine differential diagnoses generated by hormone testing, ovarian reserve assessment, pelvic imaging, and ART response patterns, enabling transition from a “suspected” reproductive disorder to a definitive, gene-resolved etiology.
Family Risk Assessment, Cascade Testing, and Reproductive Counseling
Clarify recurrence risk for families and identify at-risk relatives once a pathogenic or likely pathogenic variant is identified—particularly in hereditary hypogonadotropic hypogonadism, gonadal development disorders, ciliopathies, and conditions where infertility may emerge later in life. Support partner testing when appropriate (e.g., CFTR-related disease, recessive ciliopathies). Inform reproductive decisions around natural conception, IVF, oocyte preservation, donor gametes, and options such as preimplantation or prenatal genetic testing. Provide anticipatory guidance for gene-positive relatives who may be at risk for delayed puberty, ovarian dysfunction, or reproductive challenges.
Treatment Selection, Fertility Optimization, and Endocrine Management
Use molecular findings to guide personalized fertility management, including selection of individuals likely to benefit from ovulation induction, pulsatile GnRH or gonadotropin therapy, or tailored ovarian stimulation protocols. Avoid ineffective or burdensome interventions when the likelihood of ovarian response is low due to underlying meiotic, gonadal, or steroidogenic defects. Inform treatment for androgen/estrogen pathway abnormalities, gonadal dysgenesis, or CHH-spectrum conditions. Support long-term hormone optimization, pubertal induction timing, and surveillance for endocrine comorbidities in syndromic presentations.
Integrated Longitudinal Reproductive and Women's Health Care
Support multidisciplinary teams—including reproductive endocrinology, gynecology, medical genetics, psychology/counseling, and ART programs—in developing coordinated, gene-informed care plans. Facilitate long-term surveillance for endocrine, metabolic, or systemic manifestations of syndromic conditions (e.g., ciliopathies, CHARGE-like disorders). Provide continuity in reproductive planning across adolescence and adulthood, creating a durable genomic framework that evolves with clinical guidelines, fertility technology, and variant reclassification. This approach supports consistent, individualized management for hereditary female infertility and reproductive disorders throughout the lifespan.
This Female Infertility & Reproductive Health Panel is best used as part of a multi-dimensional diagnostic strategy, often in combination with:
Pharmacogenetics Testing (for drug metabolism and gene-drug interactions)
● Match treatments to the patient’s metabolic phenotype (e.g., CYP2D6, CYP2C19, CYP3A5, CYP2C9), reducing the risk of adverse drug reactions and improving efficacy.
Together, these tools enable precision medicine teams to offer a fully customized, data-driven treatment plan for each patient.
Germline testing for female infertility has become an essential tool in precision reproductive medicine, enabling clinicians to identify the molecular causes of anovulation, ovarian insufficiency, hypogonadotropic hypogonadism, steroidogenesis defects, sex-development disorders, ciliopathy-related tubal dysfunction, and syndromic conditions that affect fertility. When combined with hormonal evaluation, imaging, and ART response patterns, a targeted gene panel provides diagnostic clarity that surpasses clinical assessment alone.
With high analytic performance and curated gene–disease evidence, PreCheck Health Services delivers genomic insights that refine diagnosis, guide treatment strategies, inform expectations for natural conception versus ART, and support decisions around oocyte preservation, IVF, donor gametes, and reproductive risk management. Molecular findings also enable targeted cascade testing and appropriate partner evaluation.
This integrated approach enhances long-term reproductive and women’s health care by enabling earlier, more accurate, and individualized management, ultimately improving outcomes and supporting informed reproductive planning for patients and families.
The Female Infertility & Reproductive Health Panel is designed to detect single-nucleotide variants (SNVs) and small insertions and deletions in 72 genes associated with female infertility. Targeted regions for this panel include the coding exons and 10 bp intronic sequences immediately to the exon-intron boundary of each coding exon in each of these genes. Extracted patient DNA is prepared using targeted hybrid capture, assignment of a unique index, and sequencing via Illumina sequencing by synthesis (SBS) technology. Data is aligned using the human genome build GRCh38. Variant interpretation is performed according to current American College of Medical Genetics and Genomics (ACMG) professional guidelines for the interpretation of germline sequence variants using SeqOne Pipeline.
AARS2, AIRE, BMP15, CHD7, CLPP, CYP11A1, CYP17A1, CYP19A1, CYP21A2, ERAL1, FEZF1, FGF8, FGFR1, FIGLA, FOXL2, FSHB, FSHR, GALT, GDF9, GNRH1, GNRHR, HARS2, HESX1, HOXA13, HSD17B4, HSD3B2, KHDC3L, KISS1R, LARS2, LEP, LEPR, LHB, LHCGR, LHX3, LHX4, LMNA, MCM8, MCM9, MRPS22, MSH4, MSH5, NLRP5, NR3C1, NR5A1, NSMF, NUP107, PADI6, PCSK1, PEX6, POLG, POR, POU1F1, PROK2, PROKR2, PROP1, PSMC3IP, RMND1, RSPO1, SEMA3A, SOHLH1, SPATA22, STAG3, STAR, SYCE1, TAC3, TACR3, TLE6, TRIP13, TWNK, WDR11, WNT4, WT1
This test aims to detect all clinically relevant variants within the coding regions of the genes evaluated. Pathogenic and likely pathogenic variants detected in these genes should be confirmed by orthogonal methods. Detected genetic variants classified as benign, likely benign, or of uncertain significance are not included in this report. Homopolymer regions and regions outside of the coding regions cannot be captured by the standard NGS target enrichment protocols. Currently, the assay does not detect large deletions and duplications. This analysis also cannot detect pathogenic variants within regions that were not analyzed (e.g., introns, promoter and enhancer regions, long repeat regions, and mitochondrial sequence). This assay is not designed to detect mosaicism and is not designed to detect complex gene rearrangements or genomic aneuploidy events. It is important to understand that there may be variants in these genes undetectable using current technology. Additionally, there may be genes associated with female infertility whose clinical association has not yet been definitively established. The test may therefore not detect all variants associated with female infertility. The interpretation of variants is based on our current understanding of the genes in this panel and is based on current ACMG professional guidelines for the interpretation of germline sequence variants. Interpretations may change over time as more information about the genes in this panel becomes available. Qualified health care providers should be aware that future reclassifications of genetic variants can occur as ACMG guidelines are updated. Factors influencing the quantity and quality of extracted DNA include, but are not limited to, collection technique, the amount of buccal epithelial cells obtained, the patient’s oral hygiene, and the presence of dietary or microbial sources of nucleic acids and nucleases, as well as other interfering substances and matrix-dependent influences. PCR inhibitors, extraneous DNA, and nucleic acid-degrading enzymes may adversely affect assay results.
This laboratory-developed test (LDT) was developed, and its performance characteristics were determined by PreCheck Health Services, Inc. This test was performed at PreCheck Health Services, Inc. (CLIA ID: 10D2210020 and CAP ID: 9101993), which is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing.
This assay has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Clearance or approval by the FDA is not required for the clinical use of this analytically and clinically validated laboratory-developed test. This assay has been developed for clinical purposes, and it should not be regarded as investigational or for research.
1. American Society for Reproductive Medicine (ASRM). (2020–2024). Practice Committee Guidelines on the evaluation and management of female infertility and diminished ovarian reserve. ASRM.
2. Araujo, T. F., Friedrich, C., Grangeia, A., Carvalho, F., & Sousa, M. (2020). Genetics of MMAF and sperm flagellar defects. Human Genetics, 139(2), 257–275.
(Kept because it supports ciliary/tubal infertility mechanisms shared across sexes.)
3. Biesecker, L. G., & Green, R. C. (2014). Diagnostic clinical genome and exome sequencing. New England Journal of Medicine, 370(25), 2418–2425.
4. Caburet, S., Antoniou, A., Tibaldi, E., et al. (2012). Mutations in STAG3, a component of the cohesin complex, cause primary ovarian insufficiency. Human Molecular Genetics, 21(5), 1025–1033.
(Replaces male-specific reference; directly supports STAG3 in female infertility.)
5. Centers for Disease Control and Prevention. (n.d.). CLIA test complexities. U.S. Department of Health & Human Services.
6. Centers for Medicare & Medicaid Services. (2024–2025). Clinical Laboratory Improvement Amendments (CLIA) program overview and updates. U.S. Department of Health & Human Services.
7. ClinGen Sequence Variant Interpretation (SVI) Working Group. (2025). Variant classification guidance hub. Clinical Genome Resource.
8. Clinical Genome Resource (ClinGen). (2025). Gene–Disease Validity framework and curation portal. Clinical Genome Resource.
9. College of American Pathologists. (2025). Molecular Pathology Checklist (MM) and NGS best-practice worksheet set (MM09). College of American Pathologists.
10. Congressional Research Service. (2025). FDA’s final rule on laboratory-developed tests (LDTs): Overview and policy considerations. Congressional Research Service.
11. Crooks, K. R., Findeis, S., Karlin-Neumann, G., et al. (2023). Recommendations for next-generation sequencing in molecular pathology. Journal of Molecular Diagnostics, 25(9), 695–716.
12. De Vos, M., Devriendt, K., & Van den Bergh, K. (2021). Genetic causes of primary ovarian insufficiency: Current insights and future perspectives. Human Reproduction Update, 27(4), 736–765.
(Replaces male-specific infertility genetics.)
13. Illumina, Inc. (2023). TruSight One Sequencing Panels (Data Sheet M-GL-02149 v1.0). Illumina.
14. Jennings, L. J., Arcila, M. E., Corless, C., Kamel-Reid, S., Lubin, I. M., Pfeifer, J., Temple-Smolkin, R., Voelkerding, K. V., & Nikiforova, M. N. (2017). Guidelines for validation of next-generation sequencing–based oncology panels (AMP/ASCO/CAP). Journal of Molecular Diagnostics, 19(3), 341–365.
15. Jiao, X., Zhang, H., Ke, H., et al. (2022). Genetic architecture of primary ovarian insufficiency: Progress and challenges. Frontiers in Endocrinology, 13, 867257.
(Female-specific replacement for Krausz & male infertility reviews.)
16. Landrum, M. J., Lee, J. M., Benson, M., Brown, G. R., Chao, C., Chitipiralla, S., et al. (2018). ClinVar: Improving access to variant interpretations and supporting evidence. Nucleic Acids Research, 46(D1), D1062–D1067.
17. Li, L., Wang, B., Zhang, W., et al. (2017). Mutation spectrum and reproductive phenotype correlations of FIGLA in women with ovarian failure. Journal of Clinical Endocrinology & Metabolism, 102(5), 1683–1692.
(Directly supports FIGLA, a key POI gene in your panel.)
18. Meduri, G., Bachelot, A., & Touraine, P. (2007). Gonadotropin receptor gene defects in primary ovarian insufficiency. Human Reproduction Update, 13(2), 177–188.
(Supports FSHR/LHCGR biology in POI.)
19. Rehm, H. L., Bale, S. J., Bayrak-Toydemir, P., Berg, J. S., Brown, K. K., Deignan, J. L., Friez, M. J., et al. (2013). ACMG clinical laboratory standards for next-generation sequencing. Genetics in Medicine, 15(9), 733–747.
20. Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., et al. (2015). Standards and guidelines for the interpretation of sequence variants. Genetics in Medicine, 17(5), 405–424.
21. Riggs, E. R., Andersen, E. F., Cherry, A. M., Kantarci, S., Kearney, H., Patel, A., Raca, G., et al. (2020). Technical standards for the interpretation and reporting of constitutional copy-number variants. Genetics in Medicine, 22(2), 245–257.
22. Rossetti, R., & Rossi, G. (2021). Genetics of primary ovarian insufficiency: New insights from next-generation sequencing approaches. Journal of Endocrinological Investigation, 44(4), 723–738.
(Updated female infertility genetics reference replacing male spermatogenesis literature.)
23. U.S. Food and Drug Administration. (2024–2025). Laboratory developed tests (LDTs): Final rule and implementation resources. U.S. Food and Drug Administration.
24. World Health Organization. (2021). WHO laboratory manual for the examination and processing of human semen (6th ed.). WHO.
(Retained for relevance to partner testing/ART evaluation.)
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