# Biallelic FGF4 Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency

## TL;DR

A new genetic cause for thoracic dystrophy and respiratory insufficiency is identified through FGF4 gene variants in two families.

## Contribution

Biallelic FGF4 variants are newly linked to thoracic dystrophy and respiratory insufficiency in humans.

## Key findings

- Two unrelated families with thoracic dystrophy and respiratory insufficiency have biallelic FGF4 missense substitutions.
- FGF4 alterations are proposed as a new cause for thoracic dystrophy without other typical diagnostic signs.
- The FGF4 gene is essential for thoracic skeleton development in mice and now implicated in human disease.

## Abstract

The thoracic dystrophies are inherited skeletal conditions where abnormal embryonic development of the thoracic skeleton results in a narrow chest, pulmonary hypoplasia, and respiratory insufficiency, which can be severe or lethal. The majority of thoracic dystrophies are due to biallelic alterations in genes needed for normal ciliary function. However, despite the identification of over 20 genes as causal for the thoracic dystrophy phenotype, around 20% of patients remain without a molecular diagnosis. We present two unrelated families with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency without a molecular diagnosis on previous genetic testing. Both harbor rare biallelic and predicted deleterious missense substitutions in FGF4, a gene known to be essential for formation of the thoracic skeleton in mice. We demonstrate that the phenotype is restricted to short ribs, abnormally narrow chest, and respiratory insufficiency, without other diagnostic clinical or radiological signs. We suggest that biallelic alterations in FGF4 are a newly identified disease association of thoracic dystrophy.

We report three people from two unrelated families with a clinical diagnosis of thoracic dystrophy characterized by short or missing ribs, narrow chest, and respiratory insufficiency. Affected people each have rare, biallelic, predicted deleterious missense substitutions in FGF4, a gene known to be essential for the formation of the thoracic skeleton in mice.