Identification of a putative founder variant in SLC30A10 associated with hypermanganesemia with dystonia 1 in Iranian patients: a case series and literature review

Abstract

Hypermanganesemia with dystonia 1 (HMNDYT1) is an rare autosomal recessive condition resulting from pathogenic variants in the SLC30A10 gene. The presence of biallelic variants in this gene results in systemic accumulation of manganese, which leads to dystonia, polycythemia, and liver dysfunction. We conducted clinical and genetic evaluations of seven affected individuals from six Iranian consanguineous families, emphasizing the identification of potential founder mutations, and integrated this information with a total of 80 previously reported cases. Analysis of exome sequencing in all seven individuals affected revealed the presence of the identical homozygous variant in SLC30A10 (c.1006 C > T; p.His336Tyr), suggesting a potential founder effect. The estimated most recent common ancestor for these patients lived approximately 47 generations ago, suggesting an ancient mutation originating from a common ancestor. A literature review of 80 reported HMNDYT1 cases demonstrated that hypermanganesemia, T1 hyperintensity of the basal ganglia and dentate nuclei, dystonia, and polycythemia constitute the predominant clinical features. Symptom onset occurred primarily within the first five years of life (median: ~2 years, range: 0.25–57 years). Collectively, these observations underscore the need to identify potential founder variants and to more comprehensively characterize the genotypic and phenotypic spectrum of SLC30A10 to inform genetic counseling and population-based screening strategies.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12920-026-02350-5.

Introduction

Manganese (Mn) is an essential trace element required for proper body function, as it contributes to the activation of various enzymatic reactions [1]. However, excessive Mn exposure can lead to toxic effects, including tremors, facial muscle spasms, and walking difficulty, as well as less common symptoms such as irritability, aggressiveness, and hallucinations [2, 3]. Excess manganese (Mn) accumulates in the brain’s basal ganglia, causing significant motor and cognitive impairments [4].

Three distinct genes, SLC30A10, SLC39A14, and SLC39A8, have been identified as Mn level-regulating genes [5]. SLC39A14 is a membrane transporter that moves manganese from the blood into liver cells. Mutations in this gene cause hypermanganesemia with dystonia 2 (HMNDYT2; OMIM 617013), characterized by childhood-onset parkinsonism and dystonia [6]. Similarly, SLC39A8 encodes a protein crucial for intestinal zinc absorption, and its mutations lead to congenital disorder of glycosylation type IIn (OMIM 616721, marked by infantile-onset developmental delay and hypotonia [7].

SLC30A10 is a cell membrane ion channel that excretes excess amounts of manganese out of the cell. This protein is predominantly expressed in the membranes of liver and neuronal cells and has a vital role in these cells’ survival [8]. In the liver, excess manganese is secreted into bile and removed from the body. Loss-of-function mutations in the SLC30A10 gene are the established cause of an autosomal recessive disorder known as hypermagnesemia with dystonia 1 (HMNDYT1; OMIM 613280) [9].

Consanguinity helps identify ancestral autosomal recessive disorders, as it increases the prevalence of diseases caused by founder variants inherited from a common ancestor. Detecting these founder variants is important for understanding their population-specific patterns and for developing effective public health and screening strategies [10, 11].

This study aims to expand the current understanding of the mutational landscape and clinical spectrum associated with pathogenic SLC30A10 variants, with particular emphasis on identifying potential founder effects and elucidating their implications for disease mechanism, population genetics, and targeted screening strategies in at-risk communities.

Methods

Family recruitment

All families were included in this study, were referred to the Genetic Foundation of Khorasan Razavi center from 2018 to 2024 for genetic evaluation. The families in this study carried SLC30A10 variants, as tested by exome sequencing (ES). HMNDYT1 was diagnosed in these families based on elevated whole-blood manganese, movement disorder resulting from manganese accumulation in the basal ganglia, and pathogenic variants in SLC30A10. All patients were clinically evaluated for HMNDYT1 according to the diagnostic criteria described by Fang et al., 2021, including assessment of dystonia, hypermanganesemia, polycythemia, and liver involvement [12]. Clinical and laboratory data were systematically collected to confirm the diagnosis before genetic testing.

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki. Participants provided informed and voluntary consent for the publication of their information.

Exome sequencing and Sanger sequencing

ES was performed to enrich all exonic regions of protein-coding genes using the Agilent SureSelect Human All Exon V7 kit. Genomic DNA (gDNA), previously assessed for quality, was randomly fragmented using a Covaris ultrasonic high-performance sample processing system. Next-generation sequencing (NGS) was then conducted on the Illumina MiSeq platform, generating approximately 100 million reads per sample. The sequencing platform achieved coverage of over 95% of the targeted regions, with a sensitivity exceeding 99%.

Read alignment was carried out using the BWA-MEM algorithm against the human reference genome (hg19), and variant calling was performed using the HaplotypeCaller tool from the Genome Analysis Toolkit (GATK v4.0.2). This methodology enables the simultaneous detection of single nucleotide variants (SNVs), small insertions/deletions (indels), and duplications of less than 20 base pairs.

Initial variant filtering was performed in Microsoft Excel by excluding variants with a minor allele frequency (MAF) > 1% in population databases (gnomAD v4.1.0, 1000 Genomes, ExAC). The primary gene list (PGL) included genes previously associated with HMNDYT1 and related dystonia syndrome. Initial analysis was inconclusive due to the rarity of the variants and the lack of prior reports for some candidate genes. Subsequently, three experienced analysts performed a broader analysis, incorporating all rare variants in exome data and evaluating their potential pathogenicity. Variant interpretation was supported by international databases, including ClinVar, Franklin, and Varsome, which were used both for ACMG classification and for literature curation. All identified variants were confirmed by Sanger sequencing, and parental testing was performed to determine heterozygous carrier status in all available parents.

Homozygous variants were given particular attention in accordance with the family pedigree. However, this targeted approach did not yield conclusive findings. As a result, a broader analysis strategy was adopted. The patient’s variant data were independently reviewed in Excel by three experienced analysts, who subsequently reached a consensus on the most plausible candidate variants through discussion.

Bioinformatic interpretation of variants was supported by the use of international databases, including Franklin and VarSome, as well as standard software such as Varaft. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants [13]. For confirmation, specific primers were designed using Primer3 software, and the identified candidate variants were validated through Sanger sequencing using the Applied Biosystems 3500 Genetic Analyzer.

Homozygosity mapping and age of variant

Runs of homozygosity were identified from ES data using PLINK software, and the Gamma approach was applied to estimate the age of the variant [14]. We acknowledge that exome data provides incomplete marker coverage due to the absence of intronic and intergenic SNPs, which limits the resolution of ROH and haploblock inference. Therefore, the age estimate based on LD decay should be interpreted with caution, as this method is most accurate with high-density SNP data. Despite these limitations, WES-based ROH analysis provides a useful approximation of homozygous regions in consanguineous families and can guide the identification of candidate pathogenic variants.

Result

Case series

In this study, six unrelated consanguineous Iranian families were evaluated, and a total of seven affected individuals were included (Fig. 1A). Of the six families studied, four were of Baluch and two of Persian ethnic origin (Supplementary Table 1).

Fig. 1.

A Pedigree of the six families with the proband indicated by an arrow. B Sanger sequencing of genomic DNA verified the homozygous c.1006 C > T variant in SLC30A10 in the proband and heterozygous in the parent. Visualization of the homozygous variant in the proband was performed using the Integrative Genomics Viewer (IGV)

Common clinical findings of all patients included dystonia, gait abnormality, polycythemia, and T1 hyperintensities in both globus pallidus and dentate nuclei. Laboratory investigations showed elevated levels of manganese in all patients, and in four patients, ALT, AST, RBC, and hemoglobin were elevated (Supplementary Table 2). The clinical features observed in our patients are largely consistent with those previously reported in HMNDYT1. All individuals presented with early-onset dystonia, hypermanganesemia, polycythemia, and characteristic T1 hyperintensities in the basal ganglia and dentate nuclei. No major novel phenotypic features were identified in this cohort. The age of onset and overall clinical course were also comparable to previously published cases, further supporting the phenotypic consistency of SLC30A10-related disease across different populations.

Genetic evaluation, founder effect, and estimated age of variant

ES was performed for six patients, revealing a homozygous previously reported mutation in the SLC30A10 gene (c.1006 C > T; p.His336Tyr) in all cases (Fig. 1B).The SLC30A10 c.1006 C > T (p.His336Tyr) variant (chr1:219915901 G > A) is extremely rare in population databases, with a total allele frequency of 6.2 × 10⁻⁷ in gnomAD v4.1.0 and only one heterozygous carrier of South Asian ancestry; no homozygotes were reported. In silico predictors support its pathogenicity: CADD 26.3, PhyloP 8.79, PolyPhen-2 0.999, AlphaMissense 0.6655, and REVEL 0.601.

Based on the literature review, all reported Iranian cases had the same pathogenic variant in the SLC30A10 gene. Notably, this identical variant has also been reported in a patient from India and Pakistan, a neighboring country to the Baluchistan region, whose population shares common ancestry with the Baluch ethnic group of Iran. This geographic and genetic overlap strongly suggests a founder effect within the Iranian population, particularly among individuals of Baluch origin. The recurrence of the same variant across related regional populations implies inheritance from a common ancestor, likely maintained through consanguineous marriage over generations.

Based on the identified homozygous regions (shared haplotype of approximately 1.1 Mb) (Fig. 2) and shared common ancestors, the age of the mutation was estimated with the Gamma approach. The last common ancestor was estimated to have lived 47 generations ago (95% CI 26.5 to 84.1). Assuming a generation time of 27 years, the most recent common ancestor (MRCA) of these patients with the SLC30A10 c.1006 C > T mutation would have lived about 1175 years ago (95% CI 675 to 2100), indicating an ancient emergence of this founder variant within the population. According to ACMG/AMP guidelines, the SLC30A10 c.1006 C > T (p.His336Tyr) variant was classified as likely pathogenic based on multiple lines of evidence: PM2, PP3, PP1 and PP4.

Fig. 2.

Genomic mapping identified a shared homozygous region on chromosome 1 containing the SLC30A10 gene harboring the c.1006 C > T variant. The figure highlights the approximately 1.15 Mb common haplotype, along with the positions of the corresponding SNP location

Literature review

So far, 80 patients from 54 families (including our 7 patients) with SLC30A10 (40 males, 33 females, and seven of unknown sex), representing 34 variants, have been reported (Supplementary Table 1). 17 families have a positive family history. Consanguinity was reported in 79% of cases (Supplementary Table 1).

Among the patients, the most common ethnicities include Arab, Indian, and Iranian. Hyperintense signals in the basal ganglia, hypermanganesemia, dystonia, and polycythemia are the most frequent manifestations among these patients (Fig. 3A, see comprehensive literature review in Supplementary Table 2).

Fig. 3.

A The most common clinical manifestation in patients with HMNDYT1. B Distribution of SLC30A10 variant types, with missense variants being the most common, followed by frameshift, nonsense, and in-frame indel variants. C Genomic localization of variants across the exons of the SLC29A3 gene

Missense variants represented approximately 47% of all reported variants, with c.1006 C > T being the most frequently observed variant (Fig. 3B and Supplementary Table 1). Exons 1, 4, 3, and 2 had the highest variant rates, respectively, and more than half of these variants are located within the cytoplasmic topological domains of the protein (Fig. 3C).

While most patients developed symptoms within the first five years of life, two cases presented with atypical adult-onset disease. The median age of onset was approximately 2 years (range: 0.25–57 years), and the mean age was 5.06 years (6.89 years when including adult-onset cases) (Supplementary Table 2).

Beyond age at onset, integration of clinical data from previously reported cases allows a more comprehensive characterization of the natural history of HMNDYT1. The disease typically presents in early childhood with dystonia and progresses to involve gait impairment and generalized motor dysfunction. Hepatic involvement, ranging from elevated liver enzymes to cirrhosis, may occur early or develop over time. Hematological abnormalities, particularly polycythemia, are a consistent feature and may serve as an early diagnostic clue. Neuroimaging findings, especially T1 hyperintensities in the basal ganglia, appear early and remain a hallmark of the disease. Collectively, these findings suggest a progressive multisystem disorder with relatively consistent core features but variable severity and progression across individuals.

Discussion

This study reports seven SLC30A10 cases from six consanguineous Iranian families with the same pathogenic variants (SLC30A10: c.1006 C > T) through ES. Also, we conduct a literature review to analyze the phenotype and genotype spectrum of 80 reported cases. Thus, our findings have valuable insights into genotype-phenotype evaluation and possible founder effects within the Iranian population.

The identification of the same pathogenic variants in six unrelated consanguineous families may indicate a founder effect. This is supported by all reported variants in Iranian patients were the c.1006 C > T mutation, and a shared haplotype of approximately 1.1 Mb has been identified among the affected individuals (Fig. 2).

Estimation of the mutation age indicated that the most recent common ancestor (MRCA) for this variant lived approximately 1175 years ago, suggesting an ancient origin. The presence of the same variant in populations from southeastern Iran (Baluchistan), as well as in India and Pakistan, supports a shared ancestral origin in this geographic region. Analysis of runs of homozygosity (ROH) further demonstrated that individuals of Baluch ethnicity exhibited larger ROH segments compared to those of Persian ancestry, consistent with a higher degree of consanguinity and genetic isolation. These findings suggest that the variant likely originated in the Baluch population and subsequently spread to other regions through migration.

Interestingly, only a single heterozygous carrier of the c.1006 C > T (p.His336Tyr) variant has been reported in the gnomAD v4 database, annotated with South Asian ancestry. This is in contrast to the recurrent identification of this variant among affected individuals in our cohort and previous reports from Iran, India, and Pakistan. This apparent discrepancy may be explained by the underrepresentation of certain populations, particularly Middle Eastern and Baluch ethnic groups, in large-scale public genomic databases such as gnomAD. Consequently, population-specific or founder variants may be substantially underestimated in these resources, highlighting the importance of regional genetic studies to complement global datasets.

These findings are significant for the study of population genetics and founder mutations, particularly within consanguineous populations, and may provide new opportunities for genetic counseling and carrier screening [10, 15, 16]. Moreover, by tracing ancestral variants, this work enhances our understanding of population-specific genetic risk factors and can help guide public health to reduce the prevalence of autosomal recessive disorders in regions where consanguineous marriages are common [17].

Clinical findings of our cases were similar of other studies reporting HMNDYT1 with c.1006 C > T variant. All affected individuals in this series presented hypermanganesemia, T1 hyperintensity of the basal ganglia and dentate nuclei on MRI, dystonia, and polycythemia.

MRI is an effective tool for diagnosing hypermagnesemia, with T1 hyperintensity signals of the basal ganglia and dentate nuclei being significant features. This pattern is reversed for copper deposition in Wilson’s disease [12].

The neurological symptoms, particularly gait abnormality and dystonia, were the most prominent and disabling features, reflecting the profound susceptibility of the basal ganglia to manganese neurotoxicity. The impact of Mn toxicity on the brain can be extensive and irreversible. However, several studies have demonstrated the positive effects of using chelation therapy for improving neurological performance [12, 18].

The observed hematological abnormality is mechanistically explained by the established role of manganese in upregulating erythropoietin expression, a feature that serves as a key differential diagnostic marker from other disorders of metal accumulation [19].

In conclusion, our findings broaden the clinical and mutational spectrum associated with SLC30A10 and provide evidence supporting a potential founder effect in the studied population. Identification of this shared ancestral variant carries important implications for genetic counseling, carrier testing, and early detection in at-risk groups. Future studies integrating functional assays will be essential to fully elucidate the pathogenic mechanisms and clinical relevance of SLC30A10 variants, an aspect that could not be addressed here due to the limited availability of patient-derived biological material.

Authors’ contributions

A.E., F.A., S.G.K., and M.M. contributed to study design and/or performed experiments. A.S., K.N.K., M.S.K., and L.H. contributed to writing the original draft. M.A., A.S. and M.S.A.M. contributed to the review and editing. A.E., A.R.M., S.F., Y.Y., and M.B.T. contributed to clinical data and material collection, followed the patient, analyzed data, and provided clinical care. M.B.T. and M.M. contributed to supervision.

Funding

This study was not supported.

Data availability

The datasets generated and/or analysed during the current study are available in the ClinVar repository, under accession number VCV000375609.8.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Mashhad University of Medical Sciences, conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from all participants or from the parents or legal guardians of participants under 16 years of age.

Consent for publication

Written informed consent for publication of their personal or clinical details along with any identifying images has been obtained from all the participants and the parents/legal guardians of minors.

Competing interests

The authors declare no competing interests.