Missense variant c.298G > T in the IHH gene: Expanding the phenotypic spectrum of Brachydactyly type A1

Brachydactyly type A1 (BDA1) is an autosomal dominant disorder, marked by skeletal abnormalities in the middle and distal phalanges of the digits, a condition first linked to the Indian hedgehog (IHH) gene by Bell in 1951. In this report, we delineate a novel mutation within the IHH gene observed in a Chinese family with consanguineous marriages. The affected individuals exhibit phenotypic traits such as reduced stature and limb length, along with shortened fingers and toes, yet they do not display cognitive impairments. Employing Whole-exome Sequencing (WES), we identified a previously unreported heterozygous mutation, c.298G > T (p.D100Y), located in exon 1 of the IHH gene (NM_002181.3). This mutation was confirmed in the proband and corroborated in other affected relatives through PCR and Sanger sequencing. Subsequent bioinformatics analysis utilizing tools such as MutationTaster, PolyPhen-2, SIFT, and Swissmodel suggests that this variant is likely to be pathogenic. Consequently, we hypothesize that the c.298G > T mutation in the IHH gene may lead to a functional impairment of the IHH protein, thereby inducing the skeletal abnormalities characteristic of BDA1 in the affected members of this family. Future functional studies are warranted to ascertain the pathogenic potential of this mutation.