Novel FOXP2 Variant Associated with Speech and Language Dysfunction in a Chinese Family and literature review

doi:10.21203/rs.3.rs-3892712/v1

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Novel FOXP2 Variant Associated with Speech and Language Dysfunction in a Chinese Family and literature review

https://doi.org/10.21203/rs.3.rs-3892712/v1

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published 28 Feb, 2024

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Background

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.

Methods

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.

Results

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.

Conclusions

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 for the prenatal diagnostic evaluations of prospective progeny within this familial lineage.

FOXP2

speech-language disorder

genotype and phenotype

Speech and language impairments (SLI) constitute a pervasive neurodevelopmental disorder characterized by a multifaceted etiological basis and an extensive overlap of phenotypic expressions, thus complicating clinical diagnostic paradigms[1]. Accompanying the accelerated advancements in molecular detection technologies, a progressively intricate genetic architecture underlying SLI has been elucidated, encompassing chromosomal microdeletions/microduplications as well as monogenic forms[2–5]. The Forkhead Box P (FOXP) protein subfamily, a subset of transcriptional regulators within the broader FOX family, serves a critical role in neural ontogenesis, neuronal communication, and signal transduction pathways[6, 7]. In 2001, FOXP2 emerged as a seminal molecular contributor to speech-language disorders, thus providing a foundation for subsequent discoveries[8, 9]. FOXP1 has been implicated in intellectual developmental disorders, manifesting language impairment with or without concomitant autistic features[10]. FOXP4 has recently been posited as a putative genetic determinant for neurodevelopmental disorders (NDD)[6], while mutations in FOXP3 are linked to X-linked immune dysregulation, polyendocrinopathy, and enteropathy (IPEX)[11].

Over the course of the past two decades, a relatively constrained number of cases manifesting FOXP2 variants have been reported globally. As of March 2023, a mere 59 mutational loci pertaining to FOXP2 have been archived within the Human Gene Mutation Database (HGMD). Within this repository, extensive chromosomal deletions encompassing the entire FOXP2 gene constituted the majority, succeeded by missense and nonsense mutations, with small deletions being reported only in four instances[12]. The clinical phenotype predominantly associated with FOXP2-related disorders encompasses developmental verbal dyskinesia (DVD) or childhood apraxia of speech (CAS), a complex disorder implicating deficits in speech motor planning and execution affecting sound production, syllabic sequencing, temporal features, and stress patterning. The lexical inaccuracies exhibited by affected individuals exhibit considerable variability, intensifying concomitant to the complexity of the discourse. Additionally, a broader range of phenotypic manifestations have been observed in select individuals, including oral motor deficits, global developmental retardation, and/or autism spectrum disorders[13].

In the present investigation, we report a novel frameshift variant c.661delG (p.Leu221Phefs*41) within the FOXP2 gene identified in a Chinese pedigree afflicted by speech and language impairment, as elucidated through whole-exome sequencing (WES). This unique variant was substantiated to co-segregate with the pathological manifestations amongst seven family members. Concurrently, we conducted an exhaustive review of FOXP2-related patients harboring comprehensive clinical data, endeavoring to elucidate the potential correlations between genotypic and phenotypic presentations.

2.1 Clinical information of a patient

The proband (III-2) is a male child of three years, constituting the second offspring of a non-consanguineous Chinese union (Fig. 1A). Born following an uncomplicated, full-term gestational period, the patient presented to medical professionals with pronounced linguistic deficits and intellectual disability. His language impairment is severe, characterized by an incapacity to articulate words, comprehend verbal directives, and engage in meaningful communication with others. His verbalizations are limited to rudimentary vocalizations such as "en, en," devoid of any response to name-calling. Motor skills exhibited mild developmental delays; the proband only initiated independent ambulation at the age of two. His movement is further characterized by a reluctance for independent locomotion, preferring to grasp an adult's hand, and a manifest inability to execute tasks requiring foot-jumping. Fine motor skills are also compromised, as evidenced by his incapacity to manipulate chopsticks or a spoon for feeding. Self-care remains an unattainable skill. Additional clinical features include excessive perspiration, hyperactivity, timidity, hypersalivation, and nocturnal bruxism. Despite undergoing a year of rehabilitative training, no discernible progress has been achieved.

Cardiopulmonary examination yielded no abnormalities, and limb mobility was within the normative range. Serum amino acids and urinary organic acid screenings were likewise unremarkable. Auditory brainstem response (ABR) assessments revealed V wave response thresholds for both left and right auditory channels at 30dB nHL. Results from Gesell Developmental Schedules (GDS) underscored profound delays in developmental quotients (DQ) across multiple domains (Gross Motor: 49; Fine Motor: 69; Adaptive Behavior: 33; Language: 18; Personal-Social Behavior: 21) at the age of three years and three months. Brain MRI scans revealed anomalous white matter signals in the triangular regions of the bilateral lateral ventricles, indicative of myelin dysplasia. Dynamic electroencephalographic (EEG) monitoring exhibited a predominant slow-wave background with an amplitude ranging between 5.0-6.0Hz θ waves in bilateral occipital regions during wakefulness.

The proband's mother exhibits a historical trajectory of speech impairment. She attained autonomous ambulation and speech at 18 months and subsequently matriculated into a secondary vocational institution. Presently, her verbal output remains minimal and incomprehensible. The proband's father and elder sibling manifest no health anomalies, and both maternal grandparents are reported to be in robust health (Fig. 1A).

2.2 Sample Collection

Ethical clearance for this study was granted by the Institutional Ethics Committee of Xi'an Children's Hospital. Written informed consent, in alignment with ethical guidelines, was secured from each participant or their legally designated guardians. Peripheral blood specimens (3 ml) were individually procured from the proband and respective family members, and subsequently stored in EDTA-anticoagulated collection tubes.

2.3 Whole Exome Sequencing (WES)

Peripheral blood samples (3 ml) from the proband (III-2) and his biological parents were subjected to genomic DNA isolation, adhering to the Qiagen DNA Blood MIDI/Mini Kit protocol (Qiagen GmbH, Hilden, Germany). Whole exome sequencing was executed employing Nanowes capture chips (Berry Genomics, Beijing, China) and the NovaSeq6000 sequencing platform (Illumina, San Diego, United States). Sequencing reads were aligned to the human reference genome (hg38/grch38) utilizing the Burrows-Wheeler Alignment Tool. Mutation loci were subsequently annotated based on the alignment results.

For the elucidation of polymorphic sites in the comparative data of the samples, and for statistical analyses on single nucleotide polymorphisms (SNPs) as well as insertion-deletion mutations, the Verita Trekker® Variants Detection System (Berry Genomics) and the Genome Analysis Toolkit (GATK) (https://software.broadinstitute.org/gatk/) were employed. Variants of inferior quality, characterized by a read depth of less than 10× and an allele fraction below 30%, were systematically excluded. Annotation and interpretation of identified variants were conducted employing the software tools ANNOVAR[14] and the Enliven® Variants Annotation Interpretation System (Berry Genomics).

To further ensure the reliability of the data, all identified variants were cross-referenced with extant population databases including the 1,000 Genomes Project (1000G), Exome Aggregation Consortium (ExAC), and the Genome Aggregation Database (gnomAD). Only variants with population frequencies below 1/1,000 across all databases were considered for further analysis. The guidelines delineated by the American College of Medical Genetics and Genomics (ACMG)[15] were consulted for the pathogenicity categorization and interpretive analysis of variant loci. Validation of suspected pathogenic variants was accomplished through Sanger sequencing.

3.1 Genetic Findings

Our analysis via Whole Exome Sequencing (WES) led to the identification of a hitherto unreported frameshift variant in the FOXP2 gene, designated as NM_014491.4:c.661delG (p.Leu221Phefs*41). This alteration engenders a shift in the open reading frame, with potential ramifications for gene functionality, denoted by the criterion PVS1. This variant is conspicuously absent in the gnomAD, supporting its pathogenicity(PM2_supporting). Sanger sequencing provided corroborative evidence for the co-segregation of this particular variant with the observed disease phenotype in the familial lineage, specifically in affected individuals denoted as I-3, I-4, II-2, II-3, II-5, III-1, and III-2 (Fig. 1B). Given that the proband's mother harbors this variant, albeit with the grandparents being non-carriers, it is tentatively postulated to be a de novo variant. However, this assertion lacks paternity and maternity confirmation (PM6). In accordance with American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is classified as pathogenic.

3.2 Literature Review

Our exploration of the Human Gene Mutation Database (HGMD® Professional 2023.3) disclosed a total of 59 FOXP2 variants. The focus herein is principally on those variants classified as "deleterious mutations" (DM), encompassing 38 mutations that include 12 missense/null variants (Fig. 1C), 21 gross deletions, and 5 complex rearrangements. An aggregation of 75 affected individuals is reported in extant literature and in this study, subdivided into 20 individuals with null variants, 5 with missense variants, and 50 with gross deletions or complex rearrangements.

Analysis of clinical presentations revealed that individuals with missense variants were the least prevalent, primarily manifesting impaired language development. Patients with both null and missense variants demonstrated an elevated prevalence of delayed speech acquisition, compromised current verbal abilities, and detriments in verbal comprehension and learning capabilities, in contrast to those with gross deletions or complex rearrangements. Over 80% of patients with null variants exhibited delayed speech and compromised current verbal abilities as predominant clinical features. Furthermore, ocular lesions and craniosynostosis were exclusively observed in individuals harboring null variants. Conversely, developmental delays, hypotonia, and facial deformities were solely manifest in individuals with gross deletions or complex rearrangements. Noteworthily, a modest percentage of patients across all mutational categories were diagnosed with (ASD)(Fig. 2, Supplementary table 1).

In the present investigation, we delineate a previously uncharacterized maternally-derived variant, c.661delC (p.Leu221Phefs*41), in the FOXP2 gene within a Chinese family exhibiting speech and language impairments. The clinical phenotype and trajectory of disease progression in our proband were commensurate with extant case reports of individuals afflicted with Speech-Language Disorder. Our insights contribute to a nuanced understanding of the genetic underpinnings of the proband's condition, augment the known mutational landscape of the FOXP2 gene, and serve as a foundational basis for future explorations into genotype-phenotype correlations. These inferences may furnish novel avenues for both prophylactic and therapeutic interventions in the domain of speech impairment, thereby aiding clinicians in the differential diagnosis, which encompasses both acquired and hereditary etiologies.

FOXP2 functions as a transcriptional modulator, possessing the capability to either activate or repress specific genomic loci, herein referred to as target genes. These target genes are ubiquitously localized within the basal ganglia neurons and the subcortical strata of the frontal lobe[16–20], thereby playing pivotal roles in neurodevelopment, neurotransmission, and synaptic formation and propagation—elements that are intrinsically associated with speech-related neurodevelopmental disorders[21]. Structurally, the FOXP2 gene is comprised of four discrete domains: a fork-head DNA binding region, a zinc-finger motif, a leucine zipper, and a poly-Q tract. The fork-head domain primarily facilitates transcriptional initiation and activation, while the zinc finger and leucine zipper motifs function as DNA-binding domains, enhancing the affinity between the transcription factors and the genomic DNA. The poly-Q tract, a glutamine repeat region localized within the N-terminal of the FOXP2 protein, does not have a documented association with the etiology of speech-language dysfunction[22]. Intriguingly, the p.Leu221Phefs*41 variant delineated in this study is situated within the poly-Q domain. This localization is conjectured to result in the loss of the downstream zinc finger, leucine zipper, and fork domains, potentially obfuscating the native DNA binding affinity of FOXP2, and consequently leading to transcriptional dysregulation. Such perturbations likely culminate in dysfunctional FOXP2 proteins, thereby attenuating the transcription of FOXP2 target genes and manifesting as clinical symptoms pertinent to the disorder.

The FOXP2 gene encodes the presumptive transcription factor fork-head box P2, comprising a polypeptide chain of 715 amino acids encoded by 17 exons [9]. Amongst the documented variations of FOXP2, sequence variants account for approximately 49%; large, non-recurrent contiguous gene deletions involving FOXP2 constitute roughly 40% (inclusive of maternal uniparental disomy of chromosome 7 involving the FOXP2 gene); structural variants (e.g., chromosomal translocation, inversion) disrupting FOXP2 make up around 11% [13]. Given these distributions, it is manifest that aside from sequence variants, gross deletions are disproportionately represented, predominantly impacting the entire FOXP2 gene and Uniparental Disomy (UPD). Consequently, in instances where Whole Exome Sequencing (WES) tests yield negative results, the deployment of Array Comparative Genomic Hybridization (aCGH) or Multiplex Ligation-Dependent Probe Amplification (MLPA) targeting FOXP2 is strongly advocated to preclude diagnostic inaccuracies.

Given the heterogeneity in evaluative metrics and methodologies across medical institutions, the present discourse is confined to a cursory analysis. A review of extant literature reveals that patients manifesting gross deletions or complex chromosomal rearrangements often display additional variable phenotypes encompassing facial dysmorphia, dystonia, growth retardation, and ocular lesions. The ostensible etiology underlying these phenotypic variances is the impact of these gross deletions or complex rearrangements on a substantially larger genomic region. Importantly, Autism Spectrum Disorder (ASD) was ubiquitously observed across all FOXP2 mutational spectra. While direct evidence linking FOXP2 mutations to ASD is elusive, several Neurodevelopental Disorders (NDDs) genetic studies corroborate FOXP2 as a risk-associated gene for ASD[23, 24]. However, the potential for a genomic segment within the 7q31.2 locus to harbor ASD-related genetic information cannot be categorically dismissed. Hence, a comprehensive assessment buttressed by an expanded clinical dataset is imperative for delineating the relationship between FOXP2 and ASD.

Moreover, clinical heterogeneity relative to FOXP2 gene variants is saliently evident, even within nuclear families. For instance, a family harboring the c.484delC(p.Q162Nfs*100) variant of FOXP2 displayed striking discrepancies in clinical manifestations and severity levels between genotype-identical mothers and offspring. The proband and the mother both exhibited craniosynostosis; however, the extent of language impairment diverged substantially, and the proband's sister displayed only progressive language retardation[25]. An analogous pattern of disparity in linguistic and intellectual faculties was observed in the family subject to the present study; the affected mother exhibited far less severe linguistic and cognitive impairments than the proband and was capable of regular educational engagement, whereas the proband was markedly compromised in communicative abilities. These observed phenotypic divergences are postulated to emanate either from underlying genetic dissimilarities or from the interaction with as-yet unidentified associated genetic loci.

In summation, the findings of the current study substantiate the involvement of the novel c.661delC (p.Leu221Phefs*41) FOXP2 variant in the etiology of speech and language disorders. Further inquiries into the mechanisms by which this FOXP2 variant engenders alterations in protein functionality and its subsequent ramifications on speech-language neural substrates are warranted. Such elucidations hold the potential to significantly impact both the prophylaxis and diagnostic paradigms of Childhood Apraxia of Speech (CAS) or Developmental Verbal Dyspraxia (DVD).

FOXP2,forkhead box P2;

ASD，autism spectrum disorder;

CAS, childhood apraxia of speech;

SLI, Speech and languageimpairments;

DVD, developmental verbal dyskinesia;

aCGH, array comparative genomic hybridization;

MLPA, Multiplex Ligation Dependent Probe Amplification

Ethical Approval and Consent to participate

This study was approved by the Institutional Ethics Committee of Xi'an Children's Hospital. The article does not contain any personally identifable information, and informed consent had been obtained.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This work was supported by Xi’an Children’s Hospital research project (2021D01) and Generic technology research platform of Shaanxi province 2023GXJS－01.

Authors' contributions

FC and YY contributed to conception and design of the study. LW collected the clinical data. CL wrote the first draft of the manuscript. HW and QC prepared figures 1-2, LZ，LM and LB coordinated and supervised data collection. All authors contributed to manuscript revision, read, and approved the submitted version.

Acknowledgement

We would like to thank all of the participation of the family members in this study. And to thank the Berry GnomicsCo.for the technical support.

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Novel FOXP2 Variant Associated with Speech and Language Dysfunction in a Chinese Family and literature review

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Journal Publication

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Abstract

Background

Methods

Results

Conclusions

Figures

1. Introduction

2. Methods

3. Results

4. Discussion

Abbreviations

Declarations

References

Supplementary Files

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