# A Novel Biallelic Variant in IHH Causing Acrocapitofemoral Dysplasia in a Pakistani Family

## TL;DR

A new genetic mutation in the IHH gene was found to cause a rare bone disorder in a Pakistani family, expanding the known genetic causes of this condition.

## Contribution

The study identifies the first case of ACFD in Pakistan and a fourth novel IHH gene variant.

## Key findings

- A novel homozygous missense variant [c.518C>A; p.(Ala173Asp)] was identified in the IHH gene.
- The variant disrupted the core structure and destabilized key regions of the IHH protein domain.
- This is the first reported case of ACFD in a Pakistani family.

## Abstract

Acrocapitofemoral dysplasia (ACFD) is a rare autosomal recessive disorder, characterized by postnatal onset of disproportionate short stature with short limbs, brachydactyly, cone‐shaped epiphysis, narrow thorax, and relatively large head. To date, only three homozygous missense mutations have been reported in the signaling amino terminal domain (201–308 amino acids) of the IHH gene in three ACFD families from Belgian, Dutch, and Turkish ethnicities.

In the present study, we have investigated two patients in a Pakistani family affected with ACFD. Whole exome sequencing (WES) followed by Sanger sequencing was carried out for mutational screening. The variant was further validated by in silico modeling and molecular dynamics simulation analysis.

Data analysis revealed a novel homozygous missense variant [c.518C>A; p.(Ala173Asp)] in exon 2 of the IHH (NM_002181.4) gene. The variant segregated within the family and was not observed in unaffected ethnically matched controls. In silico modeling and dynamic simulation analysis revealed that the variant disturbed the core structure of the domain and destabilized the loop region and the region surrounding the variant.

This study reports the first case of ACFD from Pakistan and identifies the fourth novel missense variant in the IHH gene that led to the broadening of the phenotypic and genotypic spectrum of ACFD.