Recurrent FOXP4 nonsense variant in two unrelated patients: Association with neurodevelopmental disease and congenital diaphragmatic hernia.

Document Type

Article

Publication Date

1-2023

Identifier

DOI: 10.1002/ajmg.a.63006

Abstract

De novo variants in FOXP4 were recently associated with a neurodevelopmental disorder characterized by speech and language delay, growth abnormalities, hypotonia, and variable congenital abnormalities, including congenital diaphragmatic hernia, cervical spine abnormalities, strabismus, cryptorchidism, and ptosis. The variant spectrum in this small cohort was limited to de novo missense except for one frameshift, the inheritance of which was unknown. Variants tested in vitro exhibited reduced repressor transcriptional activity, indicating loss of function is the likely mechanism of disease, but only one frameshift variant was reported. Here, we report four affected individuals from two unrelated families heterozygous for a nonsense variant, c.1893C > G, p.Tyr631*, in FOXP4. The phenotype of the affected children includes developmental delay, feeding difficulties in infancy, and similar facial features. In both cases, the variant was inherited from a parent with mild or even subclinical features. Interestingly, one patient presented with congenital diaphragmatic hernia, as reported in two other FOXP4 patients. This report implicates FOXP4 truncating variants in human disease and highlights the wide phenotypic spectrum and variable expressivity.

Journal Title

American journal of medical genetics. Part A

Volume

191

Issue

1

First Page

259

Last Page

264

MeSH Keywords

Child; Male; Humans; Hernias, Diaphragmatic, Congenital; Neurodevelopmental Disorders; Phenotype; Muscle Hypotonia; Frameshift Mutation; Intellectual Disability; Forkhead Transcription Factors

Keywords

FOXP4; congenital diaphragmatic hernia; neurodevelopmental disease; sequencing variant

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