Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability.

This article focuses on the identification of second genetic alterations that may explain the phenotypic variability observed in individuals with SHOX deficiency, the most common monogenic cause of short stature. Through targeted genetic analysis of 98 individuals from 48 families with SHOX deficiency, the study found no deleterious variants in SHOX promoter or intronic regions but identified eight heterozygous variants in genes related to growth plate function—such as CYP26C1, PTHLH, ACAN, NPR2, RUNX2, and TP53—that potentially act as genetic modifiers. Notably, families with SHOX alterations restricted to regulatory regions showed a higher prevalence of a second likely pathogenic variant (27%) compared to those with coding region alterations (2.9%), suggesting that additional variants may influence phenotype penetrance and severity. The findings highlight the complex genetic background contributing to SHOX deficiency phenotypes and suggest that digenic or oligogenic inheritance involving growth plate–related genes may underlie clinical variability.