Integrated genetic and clinical investigation of autosomal dominant hereditary uterine leiomyomas: genotype-phenotype correlation in a pakistani family.

backgroundHereditary uterine fibroids represent an understudied subset of leiomyomas with limited genetic characterization beyond fumarate hydratase (FH)-associated Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, where germline heterozygous mutations often cause uterine leiomyomas with cutaneous involvement in many carriers and increased risk of renal cell carcinoma in a minority. AIMS AND

objectivesThis study aimed to identify the genetic basis of isolated autosomal dominant uterine fibroids in a Pakistani family and establish genotype-phenotype correlations through prospective longitudinal phenotyping of proband II-2.

methodsWhole exome sequencing (WES) was performed on proband II-2, followed by multi-step variant filtering and Sanger sequencing validation across all available family members. Structural modeling (MODELLER v10.5), 100-vertebrate conservation analysis, and UCSF Chimera interaction zone analysis complemented functional assessment. Proband II-2 underwent serial ultrasound monitoring from conception through 5.5 months postpartum (~2years).

resultsWES of proband II-2 identified 81,909 raw variants across the exome, which were systematically filtered to yield a single high-confidence heterozygous candidate variant, FH c.568C>T (p.Arg190Cys; ClinVar:141355), previously reported in HLRCC but demonstrating perfect segregation with isolated uterine fibroids across all tested relatives without cutaneous/renal involvement. The variant disrupts an ultra-conserved residue, causing coil-to-β-sheet/α-helix transition, 5 Å zone contraction (15→9 residues), hydrogen bond distortion (2.0 Å→3.0-3.1 Å), and 42.5% residual enzymatic activity in germline heterozygous state, predisposing to two-hit tumorigenesis.. Proband II-2 exhibited dramatic pregnancy-exacerbated growth (76×70 mm at 6w5d → 91×123×87 mm peak at 32w6d), postpartum red/myxoid degeneration, and prolonged menorrhagia.

conclusionWe report heterozygous FH p.Arg190Cys perfectly segregating with the first documented Pakistani pedigree with isolated autosomal dominant uterine leiomyomas without clinically detected HLRCC extra-uterine features, expanding the FH phenotypic spectrum through population-specific expressivity. These findings establish FH screening protocols for familial fibroid cohorts and provide detailed genotype-phenotype correlations for improved clinical management and assessment of fibroids by physicians.