# Haplotype Phasing of Biallelic WNT10B Variants Using Long‐Read Sequencing in Split‐Hand/Foot Malformation Syndrome

## TL;DR

Long-read sequencing was used to determine the genetic cause of a rare limb malformation syndrome in a patient with two WNT10B gene variants.

## Contribution

Demonstrates the effectiveness of long-read sequencing for haplotype phasing in diagnosing autosomal recessive disorders without parental DNA.

## Key findings

- Long-read sequencing identified two WNT10B variants on separate alleles in a patient with SHFM.
- One variant was previously reported, while the other was novel and not found in gnomAD.
- Haplotype phasing confirmed the biallelic nature of the variants without parental DNA samples.

## Abstract

Split‐hand/foot malformation syndrome (SHFM) is a congenital limb malformation that is both clinically and genetically heterogeneous. Variants in WNT10B are known to cause an autosomal recessive form of SHFM. Here, we report a patient born to unrelated parents who was found to be a compound heterozygote for missense variants in WNT10B: c.994C>T, p.(Arg332Trp) and c.638T>G, p.(Phe213Cys). The variants were identified using long‐read PacBio sequencing, which enabled phasing and confirmed that they were located on different alleles. The maternally inherited variant p.(Arg332Trp) has been previously reported, whereas the paternally inherited variant p.(Phe213Cys) is novel and absent from the gnomAD database. Our findings highlight the utility of long‐read haplotype phasing, which provides valuable insights in determining the biallelic nature of variants in recessive disorders when parental DNA samples are unavailable.

Haplotype determination and phasing of compound heterozygous variants in WNT10B (autosomal recessive inheritance) in a patient with split‐hand/foot malformation syndrome. The biallelic nature of the two variants was detected by long‐read sequencing and confirmed by Sanger sequencing.