TARDBP gene mutation in a Chinese family with frontotemporal dementia: A case report and literature review

Abstract

Background

Mutations in the transactive response DNA binding protein (TARDBP) have never been reported in the population of familial frontotemporal dementia (FTD) in Chinese mainland.

Objective

This study reports for the first time a familial FTD carrying TARDBP mutations in Chinese mainland and summarizes the genetic and clinical features of TARDBP mutant families.

Methods

Case report of comprehensive clinical, genetic and neuroimaging examinations on a 68-year-old male patient diagnosed with behavioral variant FTD (bvFTD). A literature review was also conducted and clinical and genetic features of families with TARDBP mutations were summarized.

Results

We reported the bvFTD patient in Chinese with heterozygous mutation of TARDBP. Brain MRI revealed bilateral frontal and temporal atrophy, predominant in the right side. FDG-PET demonstrated frontal and temporal hypometabolism. ¹⁸F-DPA714-PET showed focally elevated bilateral temporal tracer uptake, and ¹⁸F-MNI-1126-PET revealed a reduction in synaptic uptake throughout the brain, especially in the bilateral temporal lobes. In the literature, we found 68 patients from 24 families with 6 different TARDBP mutations in an exon 6. Nine patients presented with symmetrical atrophy involving the frontal, temporal, and parietal lobes, 11 with asymmetrical atrophy, and 5 without atrophy. More than 60.3% of the patients had an onset age earlier than 65 years old and there was a predominance of men.

Conclusions

Our discovery confirmed a pedigree of FTD families and expanded the pedigree mutation spectrum of TARDBP in China. The establishment between phenotype and genotype will aid the diagnosis and treatment of FTD.

Keywords

Alzheimer's disease China frontotemporal dementia genetics transactive response DNA binding protein

Introduction

Frontotemporal dementia (FTD) is an umbrella term that encompasses a group of clinical syndromes due to an underlying neurodegenerative disease characterized by progressive changes in behavior, executive function or language.¹ Behavioral variant FTD (bvFTD), progressive non-fluent aphasia (PPA) and semantic dementia (SD) are the three subtypes of FTD.^2,3 The clinical and genetic characteristics of FTD can overlap with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), cortical basal syndrome (CBS), and progressive supranuclear palsy (PSP).^4–6 Around 10%-20% of patients with FTD have a strong family history or a known pathogenic mutation.⁷ More than 20 genetic mutations have been discovered to cause FTD spectrum disorders.⁸ The most three common causal genes of FTD are chromosome 9 open reading frame 72 (C9orf72), granulin (GRN) and microtubule-associated protein tau (MAPT).^9,10 It is rare that FTD caused by the TAR DNA-binding protein (TARDBP) mutations, probably due to the low number of cases reported.^11,12

Mutations in TARDBP gene were firstly reported as an important causative gene of ALS.^13,14 Subsequent studies have identified that TARDBP mutations are also associated with FTD and ALS-FTD.¹² The first FTD case of heterozygous p.I383V missense mutation in the TARDBP gene was described by Gelpi et al. in 2014.¹⁵ They presented an SD patient with clinical manifestations characterized by language dysfunction, whose neuropathological manifestations were a superimposed combination of different protein denaturations. Since then, the three authors described six similar cases, with the age of onset ranging from 39 and 68 years old.^16–18 The TARDBP gene encodes TAR DNA-binding protein 43 (TDP-43) which is a member of the nuclear ribonucleoproteins (hnRNPs) heterogeneous family.¹⁹ TDP-43 is mainly located in the cell nucleus. The p.I383V missense mutation involves a single amino acid change from isoleucine to valine at position 383, which is located in a conserved C-terminal region of the TDP-43 protein.²⁰ This region, involved in protein-protein interactions, is essential for TDP-43 to exert splicing inhibitory effects on specific RNA transcripts and also modulates the protein's solubility and cellular localization.^21,22 The abnormal assembly of TDP-43 in neuronal and glial cells characterized nearly half of cases of FTD. Different TDP-43 amyloid filament folding patterns characterize different neurodegenerative diseases.^23,24 To our knowledge, more than 60 TARDBP mutations related with neurodegenerative diseases have been reported.²⁵ Most mutations described including p.I383V are located in exon 6, encoding the hnRNP binding domain.²⁶

In this study, we reported a TARDBP mutation of bvFTD patient without motor neuron disease (MND) in China for the first time. In addition, we reviewed the familial FTD cases related to TARDBP mutations described in previous literature.

Methods

Clinical and neuropsychological workup

The patient was a 68-year-old man, who had been a primary school teacher since completing specialized secondary education. The patient underwent an extensive neuropsychological and language examination by a professional neurologist. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Disease severity was tested by Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale (FTLD-CDR). Language function was evaluated with the Boston Naming Test (BNT). Behavioral abnormalities were assessed with the Frontal Behavior Inventory (FBI) and neuropsychiatric inventory (NPI), and the ability to perform daily activities was evaluated with the Activities of Daily Living (ADL) scale. The patient and his sons underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) examinations including ¹⁸F fluorodeoxyglucose (¹⁸F-FDG) PET, translocator protein (TSPO) PET (18F-DPA-714) and synaptic vesicle glycoprotein 2A (SV2A) PET (¹⁸F-MNI1126).

The patient was accompanied by reliable caregivers, and his family signed the informed consent form. All procedures are carried out according to the ethical standards specified by Tianjin Human trial Committee and approved by Ethics Committee of Tianjin Huanhu Hospital.

Whole-exome sequencing (WES)

The patient's genomic DNA (gDNA) was isolated from peripheral blood leukocytes (QIAamp DNA Blood Kits; Qiagen, Valencia, CA, USA). His two sons accepted genetic testing. We performed exome capture with a SureSelect Human All Exon V6 + UTR (89 Mb) Kit (Agilent Technologies, Santa Clara, CA, USA). Paired-end sequencing was performed on a HiSeq2500 system (Illumina, San Diego, CA, USA) using a HiSeq SBS Kit V4 (Illumina), which generated 100-bp reads. The average and minimum sequencing depths were 125× and 20×, respectively. The following reference databases were used: hg38 (GRCh38) (https://genome.ucsc.edu), Human Gene Mutation Database (https://www.hgmd.cf.ac.uk), Genome Aggregation Database (gnomAD; https://gnomad. broad institute.org), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and Single Nucleotide Polymorphism Database (https://www.ncbi.nlm.nih.gov/SNP). WES data were analyzed for single-nucleotide variants and insertion/deletions in dementia-related genes. The results were comprehensively evaluated in aspects including minor allele frequency, conservation, predicted pathogenicity, disease association, and confirmation with Sanger sequencing.

Review of the literature

Related familial FTD cases with TARDBP mutations were reviewed. From each publication, we extracted the first author's name as well as the patients’ onset age of FTD, sex, family history, genotype and phenotype. Cases reported in clinical series but not described in details, carriers of TARDBP mutation in homozygosis or with double mutations, cases with mutations of uncertain pathogenicity were excluded.

Results

Detailed case descriptions

The patient was a 68-year-old male with 14 years of education. He was a middle school teacher and right-handed. At the age of 64 he gradually developed memory deterioration and behavioral disturbances, accompanied by irritability, sometimes showing aggression, social withdrawal and changes in diet (such as a preference for sweet foods). After 4 years of disease, the patient was seen in our memory clinic. He denies any history of chronic diseases or medication. The neuropsychological assessment showed multidomain cognitive decline, highlighted by delayed recall deficits, as well as significant Neuropsychiatric behavioral symptoms (Table 1). The results of physical examination indicated body temperature of 36.3°C, pulse rate of 64 beats/min, respiratory rate of 19 breaths/min, blood pressure of 116/75 mmHg, no thoracic deformity and clear lung sound bilaterally with absence of dry or moist rales. Heart sounds exhibited regular rhythm without pathological murmurs across all valve areas. Soft abdomen was without tenderness and the liver and spleen were non-palpable subcostally. Lower limbs showed no edema, and deformities of spinal limbs were absent. Time/place orientation, executive function and recent memory were impaired, while other neurological functions remained normal. The brain structure imaging of MRI analysis showed that bilateral frontal and temporal atrophy, predominant in the right side (Figure 1A). The multimodal PET imaging revealed: (1) FDG-PET demonstrated hypometabolism in the frontal and temporal lobes, indicating regional neuronal dysfunction (Figure 1B); (2) DPA714-PET showed focally elevated tracer uptake in bilateral temporal lobes, suggestive of localized neuroinflammation (Figure 1C); and (3) MNI1126-PET detected globally reduced synaptic uptake throughout the brain (predominantly in temporal lobes), consistent with widespread synaptic loss (Figure 1D).

Figure 1.

Neuroimaging of the patient. A) MRI showing bilateral frontal and temporal atrophy, predominant in the right side. B) FDG-PET showing hypometabolism in the frontal and temporal lobes. C) DPA714-PET showing focal elevated uptake in bilateral temporal lobes. D) MNI1126-PET showing globally reduced synaptic uptake throughout the brain, predominantly in bilateral temporal lobes.

Table 1.

Neuropsychological scale outcomes.

Neuropsychological tests	The patient	The older son	The younger son
MoCA [score/total score (prominent deficit subitems)]	15/30 (delayed recall, naming, abstract thinking and executive function)	28/30 (delayed recall, calculation)	30/30
MMSE [score/total score (prominent deficit subitems)]	22/30 (orientation, delayed recall, naming, writing)	27/30 (delayed recall)	30/30
CDR [score/total score]	1/3	0/3	0/3
Immediate memory [score (abnormal value)]	0 (≤18)	21 (≤18)	21 (≤18)
Delayed recall [score (abnormal value)]	0 (≤6)	13 (≤6)	8 (≤6)
DSST [number of correct answers within 90 s]	21	45	59
Digits forwards [score/total score]	8/10	9/10	8/10
Digits backwards [score/total score]	4/8	4/8	5/8
Trail making test
Part A [time in seconds/errors]	136 s/0	65 s/0	52 s/0
Part B [time in seconds/errors)	300 s/24	107 s/0	139 s/0
Boston naming test (score/total score)	5/30	24/30	28/30
FAB [score/total score]	5/18	18/18	18/18
ADL [score/total score (prominent deficit subitems)]	26/80 (using public transportation, cooking with appliances)	20/80	20/80
NPI [score/total score (prominent deficit subitems)]	13/122 (delusion, anxiety and apathy)	0/122	0/122
MBI-C [score/total score (prominent deficit subitems)]	18/102 (apathy, affective dysregulation, social inappropriateness and abnormal perception)	0/102	0/102
HAMD-17 [score/total score (prominent deficit subitems)]	4/55 (anxiety, apathy)	0/55	1/55 (anxiety)

MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive Assessment; ADAS-cog: Alzheimer's Disease Assessment Scale-Cognitive section; CDR: Clinical Dementia Rating; DSST: Digital Symbol Substitution Test; FAB: Frontal Assessment Battery; ADL: Activity of Daily Life; NPI: Neuropsychiatric Inventory Questionnaire; MBI: Mild Behavioral Impairment Checklist, HADM-17: The 17-items Hamilton Depression Rating Scale.

A heterozygous missense mutation (c.1147A>G, p.I383V [GenBank accession no. NM_007375.4]) at the exon 6 of the TARDBP gene was found in the patient through WES (Figure 2A). According to the American College of Medical Genetics (ACMG) guidelines, this variation was determined to be a pathogenic variation. The analysis of this locus by the ClinVar database also shows pathogenicity. Both of his two sons (III 2 was at the age of 42 and III 3 was 37 years old on clinical examination by a dementia and motor neuron specialist) carried the same mutated gene (Figure 2B, C). There were no additional disease-causing mutations found in any other genes. Therefore, we performed a detailed family history questioning and screening. The patient's pedigree was described in Figure 2D. The proband's father exhibited symptoms of memory decline and behavioral abnormalities before his death, but the exact age of onset is unknown and no clinical diagnosis has been made. Furthermore, posthumous genetic testing for the proband's father was not feasible. His brother had lung cancer and died at 60 years old. No other family members have reported any relevant medical history such as dementia, motor dysfunction or neurodegenerative diseases. Although the two sons of the proband are carriers of the same gene locus mutation, neither of them showed any abnormalities in terms of clinical phenotype, nor did they have any abnormalities in objective examinations such as brain structure imaging or molecular imaging (Figure 3A-C).

Figure 2.

Sequence diagram of the TARDBP gene mutation in the patient and his two sons. High-throughput gene testing revealed a c.1147A>G (p.I383V) heterozygous mutation in the TARDBP gene and the same variant were detected in his two sons.

Figure 3.

Neuroimaging of the patient's two sons. A) MRI of the brain demonstrates no evidence of structural abnormalities. B) No evidence of abnormal FDG metabolism. C) No evidence of abnormal MNI1126 metabolism.

According to the diagnostic guidelines,²⁷ we considered a diagnosis of bvFTD which was characterized by early and progressive behavior and personality changes including disinhibition, apathy, loss of sympathy and empathy for others, compulsive behavior and dietary changes.

Literature review

A summary of known cases of TARDBP mutations were provided in Table 2 that have been associated with familial phenotypic heterogeneity. 11 publications that reported TARDBP mutations in a total of 68 cases from 24 families with 6 different mutations were reviewed. The TARDBP mutations reported were all in the exon 6 (p.I383V, p.A382T, p.G295S, p.G384R, p.A382P and p.R361T). The clinical phenotypes of the cases reported in these studies were significantly different, including bvFTD (22/66, 33.3%), SD (7/66, 10.6%), PPA (1/66, 1.5%), ALS (35/66, 53.0%) and PD (9/66, 13.6%). The p.I383V variant is predominantly associated with isolated bvFTD or SD (69.2%), whereas p.G295S and p.G384R correlate more strongly with motor-predominant phenotypes (ALS) and rarely manifest as isolated FTD. Families have also been reported with different onset age and first symptoms. Thirty-eight cases (38/63, 60.3%) had an onset age of less than 65 years. Among the patients of the reported gender, the majority were male (38/60, 63.3%). Both the p.I383V and p.A382T mutations are more frequently associated with a male predominance among carriers. Behavioral changes (19/56, 33.9%) and limb weakness (19/56, 33.9%) were the most common initial symptoms, followed by dysarthria (6/56, 10.7%), language dysfunction (5/56, 8.9%), and anomia (2/56, 3.6%). Among the neurodegenerative diseases related to TARDBP gene mutations, the patterns of brain structure atrophy are also not the same. Among patients with FTD or combined with other neurodegenerative diseases, there were 9 cases (9/25, 36.0%) with symmetrical atrophy of the frontal, temporal and parietal, 11 cases (11/25, 44.0%) with asymmetrical atrophy and 5 cases (5/25, 20.0%) without any atrophy. Both right- and left-sided predominant atrophy was seen even within the same family.

Table 2.

Familial cases presenting with distinct clinical phenotypes.

Case	Ethnic origin	TARDBP mutation	Age onset	Sex	First symptom	Phenotype	Brain atrophy
The present case,1 family	Chinese	p.I383VExon 6	64NA	MM	Behavioral changesBehavioral changes	bvFTDbvFTD?	Right > leftNA
Floris et al.¹¹,5 families	Sardinian	p.A382TExon 6	383771	MMF	Behavioral changesBehavioral changesMotor impairment, muscle hypotrophy	bvFTDbvFTDALS?	Left > rightNANA
		p.A382TExon 6	45495575	MMFM	Behavioral changesBehavioral changesCognitive impairmentBehavioral changes	bvFTDbvFTDFTD?bvFTD	SymmetricalSymmetricalNANA
		p.A382TExon 6	6573	FM	Behavioral changesLimb weakness	bvFTD/ALSALS/bvFTD	Left > rightNA
		p.A382TExon 6	6770	MF	Behavioral changesBehavioral changes	SDbvFTD	Right > leftNA
		p.A382TExon 6	39657075	MMFF	Behavioral changesNANANA	bvFTDbvFTD/PDbvFTD/PDbvFTD/PD	SymmetricalNANANA
Quadri et al.⁴⁷,1 family	Sardinian	p.A382TExon 6	766874	FMF	Resting tremor and bradykinesiaAkinetic-rigid parkinsonismAkinetic-rigid parkinsonism	PD/FTDPD/FTDPD	NormalSymmetricalNA
Chiòet al.⁴⁸,3 families	Italian	p.A382TExon 6	587833	FMM	Dysphagia, dysarthria and emotional labilityLimb weaknessLimb weakness	ALS/FTDALSALS	NANANA
		p.A382TExon 6	43696433	MFMM	Dysphagia, dysarthria and emotional labilityLimb weaknessLimb weaknessLimb weakness	ALS/FTDALS/FTDALSALS/FTD	NormalNormalNormalNormal
		p.A382TExon 6	254364	FMM	Limb weaknessLimb weaknessLimb weakness	ALS/FTDALS/FTDALS/FTD	NormalNANA
Gelpi et al.¹⁵,1 family	NA	p.I383VExon 6	60NA	MM	AnomiaNA	SDFTD?	Left > rightNA
Cheng et al.¹⁶,1 family	Chinese	p.I383Vexon 6	396462	FFF	Limb weaknessAnomiaDysarthria and dysphagia	ALSSDALS/FTD	NormalLeft > rightRight > left
M González-Sánchez et.¹⁷,1 family	British	p.I383Vexon 6	494852	FMM	Language dysfunctionBehavioral changesLimb weakness	SDbvFTDALS	Right > leftNANA
Benajiba et al.¹²,1 family	French	p.G295Sexon 6	595773	FFM	Language dysfunctionDysarthria and dysphagiaLimb weakness	SD/ALSALSALS	NANANA
Millecamps et al.⁴⁹,2 families	French	p.G295Sexon6	5861	FF	DysarthriaDysarthria	ALSALS/FTD	NANA
Millecamps et al.⁴⁹,2 families	French	p.G384Rexon6	6061NA2768	FFMMF	Limb weaknessLimb weaknessLimb weaknessLimb weaknessLimb weakness	ALS/FTDALSALSALSALS	NANANANANA
Caroppo et al.¹⁸,7 families	French	p.G295Sexon 6	595773	MNAM	Language dysfunctionNANA	SDALSALS	NANANA
		p.G295Sexon 6	5265	MM	Behavioral changesLanguage dysfunction	bvFTD/ALSPPA/PD	Right > leftLeft > right
		p.A382Pexon 6	7135	NANA	Language dysfunctionNA	SD/ALSALS	SymmetricalNA
		p.I383Vexon 6	6565	MNA	Behavioral changesNA	bvFTD/ALSALS	SymmetricalNA
		p.I383Vexon 6	6351	MM	Behavioral changesBehavioral changes	bvFTDbvFTD	SymmetricalRight > left
	Dutch	p.I383Vexon 6	58NA	MNA	Behavioral changesNA	bvFTD/PDbvFTD	NANA
	Dutch	p.I383Vexon 6	68NA	MNA	Behavioral changesNA	bvFTDPD	SymmetricalNA
Synofzik et al.⁵⁰,1 family	Sardinian	p.A382T	316854	MMM	Behavioral changesNANA	bvFTDALSALS	SymmetricalNANA
Chiang et al.⁵¹,1 family	Norwegian	p.R361T	6669	NANA	Memory deficitsLimb weakness	FTD/ALSALS	NANA

Discussion

In this study, we reported a family of bvFTD carrying a missense mutation at the p.I383V locus of the TARDBP gene in China. The proband's clinical phenotype was bvFTD, and his father had similar manifestations. Both of his sons are carriers of the same locus of the same gene, however, both clinical examinations and brain imaging tests show normal results. We also reviewed familial FTD cases related to TARDBP mutations and found that this population had the characteristics of early onset and male dominance. In the review, all patients reported a family history of dementia, ALS, or PD. Among these cases, patients without motor symptoms survived for a longer time. Eleven patients with the p.A382T variant developed dementia concurrent with ALS, accounting for 36.7% (11/30) of FTD cases. While the research has shown that FTD manifests infrequently in TARDBP-ALS cohorts, with causal linkage confined to specific pathogenic variants-notably p.G295S, p.R361T, p.A382T, and p.I383V.²⁸

Genetic epidemiology studies reveal divergent TARDBP mutation frequencies across FTD cohorts. Analysis of 198 familial Dutch probands identified variants in 3.5% of cases,²⁹ whereas the research results from two independent Chinese research teams indicate that the rare mutation rate of TARDBP in the Chinese FTD cohort is 0.77% (2 out of 261 patients who were detected to have pathogenic variations) (30) and null detection in the other 248 patient cohort.³⁰ For rare mutation screening, small-to-moderate sample sizes may introduce stochastic variability in frequency estimates, as the low prevalence of such variants makes their detection highly sensitive to cohort size. Moreover, subtle genetic distinctions among regional subgroups of the Chinese population (e.g., northern versus southern China) could underlie variability in mutation carrier rates. Precise quantification of pathogenic TARDBP variant penetrance is hindered by ascertainment bias stemming from the rarity of mutation carriers. We found that the majority of patients in the TARDBP mutation family were male. GRN was higher in female,^10,31,32 but there was no significant gender difference in the FTD population related to MAPT and c9orf72 gene mutations.¹⁰ In our study, both sons of the proband were confirmed as asymptomatic carriers of the identical variant. It might be that they have not reached the age of onset. However, epidemiologic studies indicate that pathogenic TARDBP variants exhibit a disease penetrance of approximately 40% in population-based analyses.³³ Similarly, penetrance analyses of Sardinian founder mutation carrier pedigrees demonstrated that the TARDBP p.A382T variant reaches 60% expressivity by age 70 years.³⁴ Longitudinal monitoring is essential to ascertain age-dependent penetrance in these mutation carriers.

We observed atrophy and hypometabolism in the bilateral frontal and temporal lobes in the proband, especially on the right side. His memory decline was associated with atrophy of the parietal lobe and hippocampus. Some patients with hereditary FTD have already shown a decline in episodic memory test scores during the prodromal or early stages of the disease.³⁵ Thus, the presence of early episodic memory impairment cannot be used as a basis to rule out FTD. Research indicates that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy.³⁶ A significant proportion of patients with right-predominant temporal variant FTD are initially misdiagnosed in psychiatric settings due to prominent behavioral symptoms, without recognition of their underlying progressive cognitive decline.³⁷

Neuronal and axonal degeneration are sufficient to induce microglial activation, triggering an inflammatory response.³⁸ We found TSPO was upregulated in the bilateral temporal lobes in this patient, indicating local neuroinflammation. Few studies to date have examined neuroinflammation in vivo in FTD patients with different gene mutations. Immunohistochemical analysis of postmortem tissue revealed that patients with FTD (n = 78) exhibited elevated microglial activation in the frontal and temporal cortices relative to controls. Furthermore, the FTD-MART subtype demonstrated heightened microglial activation in the subcortical white matter of the temporal lobe compared to other types of FTD gene variations.³⁹ The distinct contrast between the anterior brain region inflammation pattern in FTD and the posterior cortex-dominant pattern in AD significantly improves the accuracy of differentiation.^40–42

Synaptic density reduction is often secondary to neuronal degeneration or axonal injury. SV2A is an integral glycoprotein in the membrane of synaptic vesicles, widely distributed throughout the brain. It is involved in synaptic vesicle trafficking and exocytosis and regulates synaptic function.⁴³ In the study, MNI1126-PET showed globally reduced synaptic uptake throughout the brain, predominantly in bilateral temporal lobes, indicating synaptic density loss. Patients with bvFTD exhibited severe bilateral synaptic loss in the medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe through PET.⁴⁴ Extensive synaptic loss and reduction in the number of spines have been documented post-mortem in the diseased cortex.^45,46 Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments,⁴⁴ consistent with the proband's clinical performance.

Conclusion

In conclusion, we report for the first time a FTD family in Chinese mainland that carries a missense mutation (p.I383V) in the TARDBP gene. The TARDBP gene mutation is a rare mutation in the FTD population and the mutation locus discovered so far are all concentrated in the sixth exon region. Patients with TARDBP gene mutations are mostly male and belong to early-onset dementia. Our findings have expanded the mutation spectrum of TARDBP in FTD and hope to provide a useful reference for future studies. However, the report still has some limitations. First of all, not all the reported family members have undergone neurological examinations and genetic screening. Secondly, since FTD related to TARDBP gene mutation is rare, the sample size of this review is relatively. Furthermore, multicenter genetic studies are needed to confirm the frequency and mutation sites of TARDBP mutations in order to establish the association between genotypes and phenotypes.

Footnotes

Acknowledgements

The author thanks all the subjects in this study for providing the necessary materials and also expresses gratitude to Tianjin Huanhu Hospital for its academic platform support.

ORCID iDs

Xue Zhao

Liyong Wu

Pan Li

Ethical considerations

The studies involving human participants were approved by Ethics Committee of Tianjin Huanhu Hospital.

Consent to participate

The patients/participants provided their written informed consent to participate in this study.

Consent for publication

Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.

Author contribution(s)

Xue Zhao: Conceptualization; Data curation; Methodology; Writing – original draft; Writing – review & editing.

Liyong Wu: Investigation; Writing – review & editing.

Pan Li: Formal analysis; Project administration; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from the Tianjin Municipal Health Science and Technology Project High-level Talents Special Program (TJWJ2025RC014), the Tianjin Health Industry High-Level Talent Training Project (No. Young Medical Talents TISONYXXR-D2-107) and STI 2030-Major Projects (No. 2021ZD0201802).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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