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Mol Genet Genomic Med. 2019 Jul;7(7):e00789. doi: 10.1002/mgg3.789. Epub 2019 Jun 14.

Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders.

Author information

1
Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
2
Center of Children Psychology and Behavior, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
3
Child Psychobehavioural Rehabilitation Department, Shenzhen Baoan Maternal and Child Health Hospital, Shenzhen, China.
4
Key Laboratory of Medical Information Research, Central South University, Changsha, China.
5
CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Shanghai, China.

Abstract

BACKGROUND:

Forkhead box (FOX) proteins are a family of transcription factors. Mutations of three FOX genes, including FOXP1, FOXP2, and FOXG1, have been reported in neurodevelopmental disorders (NDDs). However, due to the lack of site-specific statistical significance, the pathogenicity of missense mutations of these genes is difficult to determine.

METHODS:

DNA and RNA were extracted from peripheral blood lymphocytes. The mutation was detected by single-molecule molecular inversion probe-based targeted sequencing, and the variant was validated by Sanger sequencing. Real-time quantitative PCR and western blot were performed to assay the expression of the mRNA and protein. To assess the pattern of disorder-related missense mutations of NDD-related FOX genes, we manually curated de novo and inherited missense or inframeshift variants within FOXP1, FOXP2, and FOXG1 that co-segregated with phenotypes in NDDs. All variants were annotated by ANNOVAR.

RESULTS:

We detected a novel de novo missense mutation (NM_001244815: c.G1444A, p.E482K) of FOXP1 in a patient with intellectual disability and severe speech delay. Real-time PCR and western blot revealed a dramatic reduction of mRNA and protein expression in patient-derived lymphocytes, indicating a loss-of-function mechanism. We observed that the majority of the de novo or transmitted missense variants were located in the FOX domains, and 95% were classified as pathogenic mutations. However, 10 variants were located outside of the FOX domain and were classified as likely pathogenic or variants of uncertain significance.

CONCLUSION:

Our study shows the pathogenicity of missense and inframeshift variants of NDD-related FOX genes, which is important for clinical diagnosis and genetic counseling. Functional analysis is needed to determine the pathogenicity of the variants with uncertain clinical significance.

KEYWORDS:

FOXG1 ; FOXP1 ; FOXP2 ; de novo; forkhead box domain; missense variant; neurodevelopmental disorders

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