Monoallelic and Biallelic FOXP4 Variants Cause Short Stature, Dysmorphic Features, Neurodevelopmental, Heart, and Congenital Abnormalities

FOXP4 is a transcription factor belonging to the FOX subfamily P, which acts as a multifunctional regulator in cardiac morphogenesis, lung development, and gut development. Six heterozygous missense and loss-of-function (LoF) variants in FOXP4 were reported in a few cases to cause neurodevelopmental phenotypes with multiple congenital abnormalities. Larger studies are needed to further confirm and delineate FOXP4-related disease. In this study, exome/genome sequencing was used to identify variants in 13 participants with short stature, dysmorphic features, neurodevelopmental disorders (NDD), and congenital heart disease (CHD). Additionally, we reviewed the data of 12 published cases. Among 25 participants with FOXP4 variants, 23 carried heterozygous variants, and two were homozygous for LoF variants. Most cases presented with short stature, failure-to-thrive, and dysmorphic features. Other common features included NDD, skeletal anomalies, and CHD. All heterozygous variants recruited in this study were absent from controls, confirmed to be de novo or inherited from affected parents, and predicted to undergo nonsense-mediated decay (NMD) or disrupt canonical splicing. The two homozygous LoF variants were predicted to undergo NMD. This study provides clinical and genetic evidence to confirm the autosomal dominant disease and characterizes the recessive form of FOXP4 -related disease.

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Publication Details

Journal
npj Genomic Medicine
Published
2026-08-13
DOI
https://doi.org/10.1038/s41525-026-00609-5
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
0.00

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article

Monoallelic and Biallelic FOXP4 Variants Cause Short Stature, Dysmorphic Features, Neurodevelopmental, Heart, and Congenital Abnormalities

James R. Lupski, Rachel Franciskovich, Almohanad A. Alkayyal, Benjamin Dauriat et al.
npj Genomic Medicine
Congenital heart defects research
article

Monoallelic and Biallelic FOXP4 Variants Cause Short Stature, Dysmorphic Features, Neurodevelopmental, Heart, and Congenital Abnormalities

James R. Lupski, Rachel Franciskovich, Almohanad A. Alkayyal, Benjamin Dauriat, Naif A. M. Almontashiri, Khaled K. Abu‐Amero, Sandrine Marlin, Eissa Faqeih, Mohammed A. Alotaibi, Robin‐Tobias Jauss, Malak Alghamdi, J Hermand, Abeer Alsofyani, Arthur Sorlin, Ahmad Bakur Mahmoud, Essa Alharby, Laurana de Polli Cellin, Amel Bouchatal, Alexander Augusto de Lima Jorge, Julien Van Gils, Jennifer Friedman, Rami Abou Jamra, Nada A. Almarghalani, Jerica Lenberg, Nathalia Lisboa Gomes, Mohammed Saleh, Chaya N. Murali, Sophie Rondeau, Daniel G. Calame, Adriane Cardoso-Demartini
article en

Abstract

FOXP4 is a transcription factor belonging to the FOX subfamily P, which acts as a multifunctional regulator in cardiac morphogenesis, lung development, and gut development. Six heterozygous missense and loss-of-function (LoF) variants in FOXP4 were reported in a few cases to cause neurodevelopmental phenotypes with multiple congenital abnormalities. Larger studies are needed to further confirm and delineate FOXP4-related disease. In this study, exome/genome sequencing was used to identify variants in 13 participants with short stature, dysmorphic features, neurodevelopmental disorders (NDD), and congenital heart disease (CHD). Additionally, we reviewed the data of 12 published cases. Among 25 participants with FOXP4 variants, 23 carried heterozygous variants, and two were homozygous for LoF variants. Most cases presented with short stature, failure-to-thrive, and dysmorphic features. Other common features included NDD, skeletal anomalies, and CHD. All heterozygous variants recruited in this study were absent from controls, confirmed to be de novo or inherited from affected parents, and predicted to undergo nonsense-mediated decay (NMD) or disrupt canonical splicing. The two homozygous LoF variants were predicted to undergo NMD. This study provides clinical and genetic evidence to confirm the autosomal dominant disease and characterizes the recessive form of FOXP4 -related disease.

npj Genomic Medicine
Universidade Federal de Minas Gerais (BR), Hôpital Necker-Enfants Malades (FR), Children’s Institute (US), Université de Bordeaux (FR), Inserm (FR), Centre Hospitalier de Luxembourg (LU), Baylor College of Medicine (US), King Saud bin Abdulaziz University for Health Sciences (SA), Taibah University (SA), King Saud Medical City (SA), King Saud University (SA), Centre Hospitalier Universitaire de Bordeaux (FR), Rady Children's Hospital-San Diego (US), King Abdullah International Medical Research Center (SA), King Khaled Eye Specialist Hospital (SA), Bordeaux Population Health (FR), Grupo Santa Casa de Belo Horizonte (BR), University Hospital Leipzig (DE), Hospital de Clínicas Universidade Federal do Paraná (BR), Laboratoire National de Santé (LU), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Texas Children's Hospital (US), Institut des Maladies Génétiques Imagine (FR), Université de Limoges (FR), University of Tabuk (SA)
Johns Hopkins University, Baylor-Hopkins Center for Mendelian Genomics, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Institutes of Health, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Gender equality
Openalex Percentile: Top 16%
Congenital heart defects research
DOIOpen Access PDFOpenAlex
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