Abstract
Since its initial identification, the Forkhead Box P2 gene (FOXP2) has maintained its singular status as the archetypal monogenic determinant implicated in Mendelian forms of human speech and language impairments. Despite the passage of two decades subsequent to its discovery, extant literature remains disproportionately sparse with regard to case-specific instances and loci of mutational perturbations. The objective of the current investigation centers on furnishing an enriched delineation of both its clinical manifestations and its mutational heterogeneity. Clinical phenotypes and peripheral blood samples were assiduously amassed from familial subjects. Whole-exome sequencing and Sanger sequencing methodologies were deployed for the unambiguous identification of potential genetic variants and for corroborating their co-segregation within the family pedigree. An exhaustive review of published literature focusing on patients manifesting speech and language disorders consequent to FOXP2 genetic anomalies was also undertaken. The investigation yielded the identification of a novel heterozygous variant, c.661del (p.L221Ffs*41), localized within the FOXP2 gene in the proband, an inheritance from his symptomatic mother. The proband presented with an array of symptoms, encompassing dysarthric speech, deficits in instruction comprehension, and communicative impediments. In comparison, the mother exhibited attenuated symptoms, including rudimentary verbalization capabilities punctuated by pronounced stuttering and dysarthria. A comprehensive analysis of articles archived in the Human Gene Mutation Database (HGMD) classified under “DM” disclosed the existence of 74 patients inclusive of the subjects under current examination, sub-divided into 19 patients with null variants, 5 patients with missense variants, and 50 patients with gross deletions or complex genomic rearrangements. A conspicuous predominance of delayed speech, impoverished current verbal abilities, verbal comprehension deficits, and learning difficulties were observed in patients harboring null or missense FOXP2 variants, as compared to their counterparts with gross deletions or complex rearrangements. Developmental delays, hypotonia, and craniofacial aberrations were exclusive to the latter cohort. The elucidated findings augment the existing corpus of knowledge on the genetic architecture influencing both the proband and his mother within this specified familial context. Of critical importance, these discoveries furnish a robust molecular framework conducive to the prenatal diagnostic evaluations of prospective progeny within this familial lineage.
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The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Change history
25 March 2024
A Correction to this paper has been published: https://doi.org/10.1007/s13353-024-00851-6
Abbreviations
- FOXP2:
-
Forkhead box P2
- ASD:
-
Autism spectrum disorder
- CAS:
-
Childhood apraxia of speech
- SLI:
-
Speech and language impairments
- DVD:
-
Developmental verbal dyskinesia
- aCGH:
-
Array comparative genomic hybridization
- MLPA:
-
Multiplex ligation-dependent probe amplification
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Acknowledgements
We would like to thank all the participating family members in this study and Berry Genomics Co. for their technical support.
Funding
This work was supported by Xi’an Children’s Hospital research project (2021D01) and the Generic Technology Research platform of Shaanxi province 2023GXJS-01.
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FC and YY contributed to the conception and design of the study. LW collected the clinical data. CL wrote the first draft of the manuscript. HW and QC prepared Figs. 1 and 2. LZ, LM, and LB coordinated and supervised data collection. All authors contributed to the manuscript revision and read and approved the submitted version.
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This study was approved by the Institutional Ethics Committee of Xi’an Children’s Hospital. The article does not contain any personally identifiable information, and informed consent had been obtained.
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Communicated by Ewa Ziętkiewicz.
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The original online version of this article was revised: The original article contains an error. The authorship under the article note should be change from: “Fengyu Che, Chenhao Li, Lifang Wang, and Ying Yang contributed equally to this work.” to: “Fengyu Che and Chenhao Li contributed equally to this work”
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Che, F., Li, C., Zhang, L. et al. Novel FOXP2 variant associated with speech and language dysfunction in a Chinese family and literature review. J Appl Genetics 65, 367–373 (2024). https://doi.org/10.1007/s13353-024-00849-0
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DOI: https://doi.org/10.1007/s13353-024-00849-0