A Novel Homozygous 9385 bp Deletion in the FERMT1 (KIND1) Gene in a Malaysian Family with Kindler Epidermolysis bullosa and a Review of Large Deletions

TL;DR

A new large deletion in the FERMT1 gene is identified in a Malaysian family with Kindler Epidermolysis bullosa, a rare skin disorder.

Contribution

A novel homozygous 9.4 kb deletion in the FERMT1 gene is reported, expanding the known genetic variants associated with KEB.

Findings

A 9.4 kb homozygous deletion in exons 7 to 9 of the FERMT1 gene was identified in a patient with KEB.

The deletion causes a frameshift mutation, likely leading to a non-functional kindlin-1 protein.

Abstract

Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity. Additional presentations include blistering, poor wound healing, skin atrophy, and increased risk of skin cancer. Most cases of KEB result from aberrations in the FERMT1 (Fermitin family member 1) gene encoding kindlin-1 and include nonsense, frameshift, splicing, and missense variants. Large deletion variants have been reported in nine cases to date. Most variants are predicted to lead to premature termination of translation and to loss of kindlin-1 function. In this study, we report on a 33-year-old male patient who presented with typical clinical manifestations of KEB. As routine molecular testing failed to obtain a diagnosis, Next Generation Sequencing (NGS) of an Epidermolysis Bullosa (EB)-specific panel was carried out followed by the determination of the deletion breakpoints and verification at the mRNA and protein levels. This approach revealed a new large homozygous deletion of ~9.4 kb in the FERMT1 gene involving exons 7 to 9. Finally, we performed a literature review on large FERMT1 deletions. The deletion is predicted to skip exons 7 to 9 within the mRNA, which results in a frameshift. The patient’s phenotype is likely caused by the resulting truncated and non-functioning protein. Our report further enriches the spectrum of FERMT1 gene variants to improve genotype–phenotype correlations.

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