Genetic Associations with Pectus Excavatum: A Systematic Review

Pectus excavatum (PE) is the most common congenital chest wall deformity, affecting approximately 1 in 400 live births. Although familial clustering supports a genetic contribution, the molecular basis of PE remains poorly defined. This systematic review synthesizes existing evidence on genetic variants associated with PE to guide future genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses.

A comprehensive systematic search was conducted across all electronic databases, including Google Scholar, PubMed/MEDLINE, Web of Science, and arXiv, from inception to November 2025. Nine studies met the inclusion criteria. The search strategy utilized the terms "pectus excavatum", "genetic variants", "SNPs", and "GWAS", combined with Boolean operators. Eligible studies reported genetic associations, family-based analyses, or mechanistic investigations. The Newcastle-Ottawa Scale was used to assess study quality.

No population-level GWAS of isolated PE was identified. Fourteen genetic loci were reported across diverse study designs, including family-based exome sequencing (REST, SMAD4, COL5A1, COL5A2), case reports (COL1A1, COL27A1, NF1, BICD2, PTPN11), candidate gene analyses (ACAN), mouse models (GPR126, GAL3ST4), and linkage analysis implicating chromosome 18q. These genes converge on four key biological pathways: extracellular matrix and collagen metabolism, TGF-β/BMP signaling, cartilage development, and transcriptional regulation. Importantly, none of the included studies reported SNP-level effect sizes, allele frequencies, or odds ratios, precluding construction of valid MR instruments.

Current genetic evidence for PE is largely derived from rare variants and family-based studies, with no population-level GWAS available. This critical gap limits causal inference, underscoring the urgent need for large-scale international GWAS to identify common variants and clarify the genetic architecture of PE.