Identification of Rare Variants in IHH Signaling Pathway-Related Genes Associated with Short Stature

Objectives: Short stature is a multifactorial condition with significant genetic heterogeneity. This study aims to explore novel pathogenic genes associated with short stature. Subjects and methods Whole exome sequencing was performed on 138 patients with idiopathic short stature, familial short stature, small for gestational age (SGA) short stature, and short stature associated with other symptoms to explore their genetic basis. Sanger sequencing was used to validate the candidate genes. Conservation analysis and homology modeling were also conducted. Results We identified 22 heterozygous variants in genes related to the IHH signaling pathway in 22 patients. These include one variant in IHH (p.H382Y), two variants in SMO (p.V600M and p.T548I), three variants in PTCH1 (p.K202R, p.V965L, and p.P1131L), and three variants in PTCH2 (p.V430A, p.Q488L, and p.H376Y). Additionally, two variants in GLI1 (p.R510W and p.Q655H), two variants in GLI2 (p.E735K and p.L782P), and two variants in GLI4 (p.D327G and p.P155H) were found. SUFU had one variant (p.R343C), BOC had two variants (p.S480L and p.E620D), GAS1 had two variants (p.G289S and p.P85S), and CDON had two variants (p.C1120Y and p.I84V). These variants were confirmed to be rare through multiple genomic databases. Sequence alignment indicated that the affected amino acids are evolutionarily conserved among vertebrates. Structural modeling using SWISS-MODEL suggested that these variants may disrupt protein structure and function. Conclusion Our findings suggest that variants in genes associated with the IHH signaling pathway may represent new candidate genes for short stature, thereby expanding the spectrum of pathogenic genes related to short stature.