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Background: Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. Despite recent advancements in identifying genetic risk factors, the mechanisms of many SPTBs remain poorly understood due to the phenotypic heterogeneity and complexity. Large family-based studies decrease heterogeneity and improve power to identify genetic causes of SPTB., Objective: To identify inherited genetic factors in SPTB etiology using large families., Study Design: Using the Utah Population Database, which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks' gestation) and any SPTB (<37 weeks' gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Enrolled women with SPTB underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segments analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB., Results: We identified two genome-wide significant chromosomal regions. In single-pedigree SGS analysis, a 1.75 Mega base region in chromosome 8 (8q24.23) was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate=0.028). In duo-pedigree analysis, a 1.05 Mega base region in the same 8q24.23 locus was identified in a second pedigree (false-positive rate [duo]= 0.0019). The intersecting region at the 8q24.23 locus contains FAM135B (family with sequence similarity 135 member B) and KHDRBS3 (KH RNA binding domain containing, signal transduction associated 3) genes, which have previously been implicated in oncogenesis and ovarian cancer, respectively. Duo-pedigree SPTB analysis also identified a second genome-wide significant 67 kilo base locus in chromosome 12 (12q21.1-q21.2) that was shared by all women with SPTB in two independent pedigrees (false-positive rate [duo] =0.01). The intersecting region at the 12q21.1-q21.2 locus contains CAPS2 (calcyphosine 2) and KCNC2 (potassium voltage-gated channel subfamily C member 2) genes, both implicated in vascular-related complications of pregnancy and preterm labor., Conclusion: Using large SPTB families, we identified shared chromosomal regions (8q24.23 and 12q21.1-q21.2), providing evidence for inherited (segregating) risk loci in SPTB etiology. Further investigation into genes in SPTB etiology, including functional validation may provide avenues for novel therapeutic development and guide efforts for SPTB prevention to prolong pregnancy and improve outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Background and Aims: Lynch syndrome (LS) is caused by pathogenic mutations in mismatch repair (MMR) genes. There are limited data on differences in colorectal cancer (CRC) surveillance by MMR genes, and an international consensus on surveillance based on genes is not established. We aimed to evaluate colonoscopy and esophagogastroduodenoscopy (EGD) surveillance outcomes and compare CRC surveillance findings by the mutated gene., Methods: One hundred one patients with LS were included and colonoscopy results were compared by MMR mutation. Primary outcomes included the development and recurrence of adenoma, CRC, high-grade dysplasia, advanced adenoma, and sessile serrated lesions. Logistic regressions evaluated the relationship between genes and the development or recurrence of primary outcomes. Survival analysis evaluated primary outcomes in patients with ≥ 2 colonoscopies. EGD results were summarized., Results: Three hundred twenty seven colonoscopies were reviewed. Compared to PMS2 , MLH1 was associated with a higher risk of advanced adenoma/high-grade dysplasia/CRC development (odds ratio [OR] 9.85, 95% confidence interval [CI]: 1.97-77.24) and MSH2 was associated with a higher risk of adenoma development (OR 4.17, 95% CI: 1.11-17.61). Among those with > 2 colonoscopies, MLH1 (hazard ratio 18.98, 95% CI: 1.31-274.51) and MSH6 (hazard ratio 15.03, 95% CI: 1.16-194.65) had a higher risk of sessile serrated lesions compared to MSH2 . Among patients who had adenoma detected once, MLH1 had a higher risk of adenoma recurrence compared to MSH6 (OR 14.59, 95% CI: 1.53-244.30) and PMS2 (OR 47.15, 95% CI: 4.26-984.28). MSH2 had a higher risk of adenoma recurrence compared to PMS2 (OR 11.89, 95% CI: 1.38-164.78). Of 170 EGDs, an actionable finding was identified in 16% of patients during their first 3 EGDs., Conclusion: Surveillance colonoscopy outcomes differed in patients with LS and suggest the need to guide surveillance based on MMR gene mutation., (© 2024 The Authors.)