# Whole exome sequencing enables the correct diagnosis of Frank–Ter Haar syndrome in a Saudi family

## TL;DR

Whole exome sequencing helped correctly diagnose Frank–Ter Haar syndrome in a Saudi family with a rare genetic mutation.

## Contribution

A novel homozygous missense variant in the SH3PXD2B gene was identified as a causative mutation for Frank–Ter Haar syndrome.

## Key findings

- A rare homozygous variant (c.280C>G; p.R94G) in the SH3PXD2B gene was found in affected individuals.
- The variant was confirmed to segregate with the disease phenotype in the family.
- The mutation is predicted to be damaging and is linked to autosomal recessive Frank–Ter Haar syndrome.

## Abstract

Frank–Ter Haar syndrome (FTHS) is a rare genetic hereditary autosomal recessive disorder characterized
by defective malformation of cardiovascular, craniofacial, and skeletal system. Mutations in the SH3PXD2B gene are
a common cause in the development of FTHS. We recruited a family with two affected individuals (3-year-old female
and 2-month-old male infant) having bilateral clubfoot. Family pedigree shows an autosomal recessive mode of inheritance.
DNA was extracted from the blood samples of six members of the family. Whole exome sequencing was
done for the two affected individuals and the variant was validated in the whole family by using Sanger sequencing
approach. Whole exome sequencing (WES) data analysis identified a rare homozygous variant (c.280C>G; p.R94G) in
the SH3PXD2B gene, and Sanger sequencing showed that the same variant perfectly segregates with the phenotype
in the pedigree. Moreover, the variant is predicted to be damaging and deleterious by several computation tools. Revisiting
the family members for detailed clinical analysis, we diagnosed the patients as having the typical phenotype
of FTHS. This study enabled us to correctly diagnose the cases of FTHS in a family initially recruited for having bilateral
clubfoot by using WES. Moreover, this study identified a novel homozygous missense variant (c.280C>G; p.R94G) in
(NM_001308175.2) the SH3PXD2B gene as a causative variant for autosomal recessive FTHS. This finding supports the
evidence that homozygous mutations in the SH3PXD2B gene are the main cause in the development of FTHS.