L26/O-208 Clinical predictors of adenomyosis comorbidity in PCOS IVF patients: endocrine profiling integrated with ACMG/AMP host-variant interpretation

Abstract Study question Which clinical and endocrine factors distinguish PCOS+adenomyosis from PCOS-only, and which ACMG/AMP-classified host variants are observed in PCOS+adenomyosis versus PCOS-only in women undergoing IVF/ICSI? Summary answer PCOS+adenomyosis showed higher baseline E2 and BMI with lower AMH than PCOS-only; ACMG/AMP-classified variants included a novel FANCM change absent in controls. What is known already PCOS frequently coexists with adenomyosis, creating clinically relevant heterogeneity in ART populations. Routine endocrine markers may help identify the subset of PCOS patients with uterine comorbidity, while host genetic susceptibility could contribute via genome stability, metabolic stress, and tissue remodelling pathways. However, genetic findings require standardized interpretation. The American College of Medical Genetics and Genomics and Association for Molecular Pathology ACMG/AMP framework provides a reproducible approach to classify variants (benign/likely benign/VUS/likely pathogenic/pathogenic) and supports cautious reporting of candidate signals in clinical cohorts. Study design, size, duration Retrospective IVF/ICSI cohort. 568 women were classified into PCOS-only and PCOS+adenomyosis (clinical analysis). Tubal-factor infertility served as controls (N = 110) for genetic comparison. Primary objective: identify baseline factors associated with adenomyosis comorbidity within PCOS. Secondary objective: catalogue candidate host variants and interpret them using ACMG/AMP criteria. Participants/materials, setting, methods Baseline variables were extracted and compared between PCOS+adenomyosis, PCOS-only and controls using clustered logistic regression (GEE with robust standard errors; clustering by patient ID), reporting effects per 1 SD increase. Peripheral-blood DNA underwent candidate-variant screening; variants were annotated and classified using ACMG/AMP evidence (population frequency, predicted consequence, computational/knowledgebase support). The gene set included FANCM, RTEL1, WFS1, PRDM16, SOX9, KIF7, RPGRIP1L, DLL3, MXRA8, C1QTNF12, and NADK; a novel FANCM variant was evaluated by Fisher’s exact test. Main results and the role of chance Endocrine profiling comprised 568 IVF patients (PCOS-only n = 455; PCOS+adenomyosis n = 113) and a control group (n = 110). Within the PCOS population, baseline estradiol (E2) showed a strong association with adenomyosis comorbidity (clustered model p = 9.3 × 10-10); trigger-day E2, where available, independently supported this relationship (p = 3.05 × 10-4). Higher BMI was also significantly associated with adenomyosis (p < 0.01). Clinically, 95/113 PCOS+adenomyosis patients reported dysmenorrhoea and/or heavy menstrual bleeding. AMH differed significantly across groups: it was lower in PCOS+adenomyosis than PCOS-only (p < 0.01), yet remained higher than controls (n = 110), consistent with an intermediate endocrine phenotype.Genetic screening identified candidate variants across a targeted gene set spanning genome stability (e.g., FANCM, RTEL1), metabolic/endocrine pathways (e.g., WFS1, NADK, C1QTNF12), and developmental/ciliary signalling (e.g., KIF7, RPGRIP1L, DLL3). All variants were processed using ACMG/AMP classification to standardize interpretation and minimize “novelty-only” reporting. A novel FANCM coding variant (NC_000014.9:g.45167038C>G, GRCh38) was detected in 4 PCOS-only and 1 PCOS+adenomyosis patient (5/56 PCOS phenotypes, 8.9%) and in 0/47 sequenced controls (subset of the endocrine control cohort; two-sided Fisher’s exact p≈0.061), indicating a hypothesis-generating enrichment signal. Under ACMG/AMP, this variant is best reported as a candidate (provisional) finding requiring population-frequency confirmation and independent replication. Limitations, reasons for caution Retrospective design and incomplete BMI/AMH recording limited covariate adjustment. ACMG/AMP classification provides standardized reporting but does not substitute for functional validation; genetic enrichment is based on modest sample size and requires replication and population-frequency confirmation. Wider implications of the findings A combined endocrine + ACMG/AMP-anchored host-genomic framework may improve phenotyping of PCOS patients at risk of adenomyosis comorbidity in IVF settings, generating testable mechanistic hypotheses and supporting future risk stratification after validation. Trial registration number No