Krabbe disease (KD, OMIM #245200) is a rare autosomal recessive lysosomal storage disorder characterized by severe demyelination affecting both the central and peripheral nervous systems. Here we report the clinical and molecular findings of two unrelated Iranian patients with KD, originating from consanguineous families. Genetic analysis was initially performed using whole-exome sequencing (WES), then validated by Sanger sequencing. WES identified a novel homozygous variant in the GALC, c.836T > G (p.L279X), in patient-1. In patient-2, WES detected a previously reported homozygous variant, c.578T > C (p.I193T), in the GALC. Sanger sequencing confirmed homozygosity of these variants in the affected patients and heterozygosity in their parents. The affected brother of patient-2 was also homozygous for the variant c.578T > C. The pathogenicity of the detected variants was supported by various lines of evidence, including in silico predictive tools, segregation analysis, and population genetic databases frequency. Our findings expand the mutational spectrum of GALC and highlight the clinical heterogeneity of KD. Morover, these finding contribute to improved genotype-phenotype correlations, which are essential for accurate diagnosis, prognostic valuation, and genetic counseling.

BACKGROUND:Childhood Disintegrative Disorder (CDD), or Heller's syndrome, is a rare neurodevelopmental condition characterized by late regression of language, social, and motor abilities after a period of normal development. Its etiology remains unclear, but may involve genetic, immunologic, or environmental factors. While biological causes are emphasized in most studies, psychosocial influences have been rarely examined. This report presents a case of CDD following severe psychosocial trauma, accompanied by comprehensive genetic testing and structured sleep assessment. METHODS:A multidisciplinary evaluation including neurological, neuroimaging, and psychiatric assessments, physical examination, laboratory investigations, and whole-exome sequencing (WES) were performed. Developmental regression was assessed with the Autism Diagnostic Interview-Revised (ADI-R), and sleep disturbances with the Persian version of the Children's Sleep Habits Questionnaire (CSHQ). CASE PRESENTATION:A 9-year-old girl showed progressive regression in cognitive, linguistic, and motor skills at age 5 after witnessing her mother's death and her brother's self-immolation. Self-immolation is the most tragic and violent method of suicide, and is considered a severe traumatic event. Neurological examination, EEG, and MRI were unremarkable. WES and CNV analyses revealed no pathogenic variants, making genetic etiology unlikely. ADI-R confirmed severe regression in social and communication domains. The CSHQ score was 69 (>41), indicating significant sleep disturbances. Treatment with aripiprazole (12.5 mg/day) yielded minimal improvement during one year of follow-up. She was also referred for behavioral and developmental rehabilitation. CONCLUSION:This case highlights severe psychosocial trauma acting as a critical trigger for the onset of CDD. It emphasizes the need for pediatric nurses to recognize trauma-related regression, integrate trauma-informed care, and coordinate family assessment and support.

Objective In this retrospective descriptive study, we aimed to evaluate magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings alongside different ASPA gene mutations in patients to enhance understanding of the genetic backgrounds and to explore correlations between MRI findings and genetic mutations. Methods Whole exome sequencing (WES) was used for molecular analysis in seven Iranian patients with clinical diagnosis of Canavan disease. MRI and MRS findings were assessed in these patients. Clinical data, biochemical findings, detailed anatomical MRI involvement, and metabolites in MRS were evaluated. The full spectrum of brain abnormalities on conventional MRI and MRS, as well as clinical outcomes were compared with molecular data to provide insights into the neuroimaging and molecular findings in these patients. Results WES identified pathogenic or likely pathogenic variants in the ASPA gene in the majority of cases. MRI revealed involvement of deep and subcortical white matter, along with the globus pallidus in all cases. Yet, the putamen, caudate, and claustrum were not involved. MRS analysis demonstrated a typical N-acetylaspartate (NAA) peak with increased NAA/Creatine and NAA/Choline ratios. Conclusion Taken together, this study enhances our understanding of the genetic background of Canavan disease among the Iranian population. We propose functional assays or cohort studies for unresolved classifications.

Mitochondrial diseases, often stemming from recessive nuclear gene mutations, represent a heterogeneous group of disorders with significant morbidity and mortality. Carrier screening for these conditions is population-specific, yet data on the pathogenic variant burden in the Iranian population remain limited. This study aimed to analyze whole-exome sequencing (WES) data from 9989 Iranian individuals to identify the spectrum and frequency of recessive mitochondrial disease variants and to develop a population-specific carrier screening panel. We analyzed WES data from 9989 unrelated Iranian individuals. Variants in 1,564 nuclear genes associated with mitochondrial function were filtered for rarity (minor allele frequency < 0.01 in public databases), predicted pathogenicity, and recessive inheritance patterns (homozygous or compound heterozygous). Clinically relevant variants were manually curated, and carrier frequencies for significant recessive mitochondrial conditions were calculated. Our analysis identified variants across 15 groups of mitochondrial-related nuclear genes in 345 individuals recognized as carriers. Of these, 123 variants (35.6

Neuronal ceroid lipofuscinosis (NCL) is a group of progressive neurodegenerative disorders affecting the brain and retina. This study descriptively characterizes Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (^1H MRS) features across NCL subtypes in 16 patients and preliminarily explores potential associations with clinical severity and genetic findings. Due to the small sample size, no definitive genotype-phenotype correlations could be established; rather, we report observed imaging patterns as hypothesis-generating observations. MRI demonstrated patterns such as thalamic T2-weighted hypointensity and periventricular white matter signal abnormalities, which may reflect disease burden and progression. ^1H MRS, performed in a subset of patients, showed reduced N-Acetyl Aspartate and variable choline peaks. Notably, preliminary subtype-specific metabolic trends were observed across the four subtypes in which MRS was performed, suggesting the potential for metabolite profiling to aid in diagnosis and subtype differentiation. However, these findings are merely exploratory and require validation in larger cohorts. These preliminary findings suggest a complementary role for advanced neuroimaging alongside molecular testing in the early diagnosis and evaluation of NCL, though larger prospective studies are needed to validate these observations.

Primary hyperoxaluria type 1 (PH1) is a genetic disorder by defect in the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Here, we report the clinical and molecular data of four Iranian patients with PH1. Whole exome sequencing revealed six pathogenic or likely pathogenic variants in the AGXT gene in the assessed patients. A single case was found to have a likely pathogenic heterozygote variant in the SLC3A1 in addition to a likely pathogenic variant in the AGXT gene. Two novel variants, namely c.547G > T (p.D183Y) and c.647G > A (p.G216E) were detected in this gene in two distinctive patients. Notably, the latter novel variant was inherited in compound heterozygous state with another pathogenic variant in this gene, namely c.971_972del (p.V324Gfs∗7). Most notably, a single patient was found to be homozygote for two likely pathogenic variants in this gene, namely c.710C > T (p.P237L) and c.717_719del (p.F240del). The current study broadens knowledge regarding the spectrum of AGXT mutations among Iranian patients.

PURPOSE:Biallelic DIAPH1 pathogenic variants cause a neurodevelopmental syndrome occasionally associated with immunodeficiency. This study aims to define the clinical and immunological spectrum of DIAPH1-related neuroimmunological syndrome and explore the gene's developmental role using vertebrate models. METHODS:A total of 53 individuals with biallelic DIAPH1 variants, including 33 previously unreported patients, were studied. Clinical features were analyzed, and functional studies were conducted using knockout models in Danio rerio and Xenopus tropicalis. RESULTS:Clinical features included developmental delay, intellectual disability, progressive microcephaly, cortical visual impairment or blindness, epilepsy, and frequent occipital-predominant brain abnormalities. Almost half suffered from infections, mainly affecting their respiratory tract related to epilepsy and aspiration. Although the majority had normal lymphocyte subsets and serum immunoglobulins, T cell receptor excision circles and naïve T-lymphocyte counts were consistently low. The Xenopus model mirrored growth and eye defects seen in humans, whereas zebrafish exhibited no overt malformations but showed seizure-like behavior in Phenothiazine assays. CONCLUSION:DIAPH1 is critical for neurodevelopment, immune regulation, and DNA repair. The DNA repair defect may influence susceptibility to infection, lymphoma, or treatment-related toxicity. Although absolute T cell numbers are not consistent with SCID, impaired T cell maturation suggests that these patients could be identified by T cell excision circles newborn screening before neurological symptoms develop.

Background: Joubert syndrome (JS) is a rare neurodevelopmental ciliopathy characterized by a distinctive midbrain-hindbrain malformation, manifested by hypotonia, ataxia, developmental delay, and variable multisystem involvement. The condition exhibits marked clinical and genetic heterogeneity, with over 40 genes implicated to date. However, the mutational spectrum and phenotypic presentation of JS in Middle Eastern populations, where consanguinity is prevalent, remain poorly characterized. Methods: We retrospectively reviewed whole-exome sequencing (WES) data from patients referred to the Comprehensive Medical Genetics Center, Shiraz, Iran, between 2019 and 2024. Patients harboring variants in JS-related genes were identified, and their clinical records were analyzed to establish genotype–phenotype correlations. Results: A total of 21 cases with variants in JS-associated genes were identified. Neurological manifestations, including developmental delay/intellectual disability, speech defects, seizures, and motor impairment, were the most prevalent findings. Vision problems, renal involvement and polydactyly were also present. Molecular analysis revealed variants in 14 distinct genes, with AHI1 being the most frequently mutated (3 cases), followed by KIAA0586, CSPP1, KIAA0556, CC2D2A, and TMEM67. Eight cases carried pathogenic or likely pathogenic variants, while 12 cases had variants of uncertain significance (VUS), highlighting the diagnostic challenges in this genetically heterogeneous condition. Conclusion: This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies. The high rate of consanguinity in this cohort likely contributes to the enrichment of autosomal recessive forms. Further functional studies are warranted to clarify the pathogenicity of the numerous VUS identified, which will improve genetic counseling and prenatal decision-making for affected families.

BCL11B is a transcription factor with key roles in the central nervous system and T cell differentiation. It regulates the expression of several genes contributing to several pathways. Here, we report a 17-year old Iranian boy, suspected of an immunodeficiency syndrome with neurologic manifestations. Trio whole exome sequencing revealed a de novo heterozygous mutation in the BCL11B gene (NM_001282238:exon3: c.G703T) in the patient which leads to stop codon (p.E235X). This variant has not been previously reported in ClinVar. However, it seems to be likely pathogenic based on most predictors. In addition to reporting this novel BCL11B variant, we provided an overview of reported variants in this gene and their clinical manifestations. This data can help in establishment of appropriate diagnostic approaches for intellectual developmental disorder with dysmorphic face, speech delay, and T-cell abnormality.

Biallelic pathogenic variants in the HACE1 gene cause the ultra-rare neurodevelopmental disorder, Spastic Paraplegia and Psychomotor Retardation with or without Seizures (SPPRS). We identified a recurrent HACE1 variant in two unrelated, consanguineous Iranian families and investigated its potential founder origin, alongside a review of all reported HACE1-related cases. Whole exome sequencing (WES) was performed on the probands, and the variant was confirmed and segregated by Sanger sequencing. To assess a shared ancestral origin, we conducted runs of homozygosity (ROH) mapping, haplotype analysis, and mutation age estimation. Both probands carried the same homozygous nonsense variant HACE1 (NM_020771.4:c.1396 C > T; p.Gln466Ter), which co-segregated with the disease in both families. ROH and haplotype analyses revealed a shared 6.6 Mb homozygous region encompassing HACE1, consistent with a possible founder effect. The variant was estimated to have arisen approximately 10.3 generations ago ( 250 years). Furthermore, review of previously reported HACE1-related cases indicated that delayed psychomotor development, intellectual disability, hypotonia, spasticity, brain abnormalities, motor disorders, and speech impairment are the most prevalent features. Our findings support a putative founder effect, suggesting that the HACE1:c.1396C> T variant likely represents a founder variant within the Iranian population and, to our knowledge, mark the first report of SPPRS-causing variants from Iran. Beyond expanding the known genetic spectrum, this study highlights phenotypic heterogeneity, even among patients sharing the same genotype, and further characterizes the clinical variability and phenotypic spectrum of the disorder, thereby aiding more accurate diagnosis and genetic counseling for at-risk families.

X-linked agammaglobulinemia (XLA) is among the most frequent primary immunodeficiencies in childhood. This disorder is caused by a disruption in B cell development resulted from mutations in Bruton’s tyrosine kinase (BTK) gene. We used whole exome sequencing (WES) to find the underlying genetic basis of immunodeficiency in a group of patients with different clinical manifestations and reported 10 cases of XLA. A range of different mutation types, including nonsense (e.g., p.Gln234*), missense (e.g., p.Arg615Ser), and frameshift (e.g., p.Glu271Lysfs*6) mutations, as well as one splice site variant (c.1631 + 5G > T in Case 8) were detected in the patients. This study provides an overview of BTK variants among Iranian patients and shows the heterogeneous pattern of these variants. Based on the importance of early diagnosis and identification of genetic basis of immunodeficiency in the affected individuals, we suggest early application of WES in the course of molecular diagnosis to save time and cost.

Background: The alkaline ceramidase 3 (ACER3) gene encodes an enzyme that regulates bioactive lipids, including ceramides, sphingosine, and sphingosine-1-phosphate, whose balance is essential for cell viability. Biallelic ACER3 variants have been associated with early-onset progressive leukodystrophy/leukoencephalopathy, previously reported only in seven patients from five families. Methods: Exome and genome sequencing of individuals with undiagnosed neurodevelopmental disorders, combined with international data sharing, identified multiple families with biallelic ACER3 variants. Enzymatic assays, lipidomics, mutagenesis, and protein modelling were used to assess variant pathogenicity. Findings: We describe 61 patients from 56 families (54 patients from 51 newly reported families), defining the clinical and molecular spectrum of ACER3-related disease. Infantile onset occurred in 89%, with moderate (54%) or rapid (37%) progression. Premature death occurred in 28% (mean age 6.0±4.3 years); mean age of living patients was 6.2±5.0 years. Core features included developmental regression or stagnation (100%/89%), global developmental delay (72%), limb spasticity (92%), axial hypotonia (74%), dystonia (73%), feeding difficulties (72%), contractures (45%), scoliosis (39%), and epilepsy (32%). A consistent facial gestalt was observed in 9/17 assessed patients. Neuroimaging showed posterior-predominant periventricular and deep white matter abnormalities, typically with minimal cerebral atrophy (86%). Functional studies demonstrated markedly reduced or absent ceramidase activity for all tested variants, total alkaline ceramidase activity of 0–34.4% in patient fibroblasts, and accumulation of ceramides and dihydroceramides, identifying critical functional hotspots. Interpretation: Together, these findings enhance the clinical, molecular, and biochemical understanding of ACER3-related disease, underscore the critical role of ACER3 in maintaining sphingolipid homeostasis, and provide a foundation for future therapeutic avenues.

Knobloch Syndrome (KS) is a rare genetic disorder characterized by ocular abnormalities and central nervous system (CNS) defects, which are attributed to collagenopathy. The primary gene implicated in KS is COL18A1, which encodes the alpha chain of type XVIII collagen. This type of collagen functions as a proteoglycan, predominantly located in the basement membrane of human tissues. This study examined an Iranian female presenting with symptoms of horizontal nystagmus, strabismus, and suspected vision loss, with a potential diagnosis of KS. Genomic DNA was subjected to whole-exome sequencing (WES). The identified pathogenic variant was subsequently confirmed using Sanger sequencing. The impact of the identified pathogenic variant on the structure of COL18A1 was assessed using I-TASSER. Analysis of WES data revealed two pathogenic compound heterozygous variants, c.2416C>T (p.Arg806Ter) and c.1698delC (p.Gly567AspfsTer45), in exons 7 and 16, respectively, of the COL18A1 (NM_030582) gene. Furthermore, a standard literature review of clinical data highlighted the heterogeneity of phenotypic manifestations, ranging from mild ocular abnormalities to severe neurodevelopmental impairments. This study and literature search offer valuable insights into the genetic landscape of KS, thereby expanding our understanding of the disease and its clinical implications. The identification of novel variants in key genes sheds light on the underlying molecular mechanisms and potential therapeutic targets.

Kabuki Syndrome (KS) is a rare, multisystem congenital disorder with five foremost clinical manifestations encompassing dysmorphic facial characteristics, postnatal growth constraint, craniofacial/skeletal anomalies, mild to moderate intellectual disability, and dermatoglyphic abnormalities. We analyzed two unrelated Iranian patients suspected of having KS using whole-exome sequencing. An in silico analysis was performed to evaluate the potential effects of the discovered variants on the structure and function of the corresponding protein. A novel de novo heterozygous protein-truncating mutation was found in patient 1, NM_003482.4: c.13818C>G (p.Y4606X), and a de novo heterozygous premature stop codon was identified in patient 2, NM_003482.4: c.16360C>T (p.R5454X). These mutations cause haploinsufficiency in KMT2D and are absent in the proband’s parents. Although these mutations provide evidence of the potential pathogenicity of KMT2D in KS, further functional studies are necessary to confirm their impact. Our observations not only provide evidence for the potential pathogenicity of the two identified protein-truncating mutations but also have important implications for the accurate diagnosis and potential treatment of KS. These findings underscore the significance of genetic testing in diagnosing this disorder and expand our understanding of the role of KMT2D mutations in its pathogenesis.

Bardet–Biedl syndrome (BBS, OMIM 209900) is a rare autosomal recessive disorder characterized by a broad spectrum of clinical features including renal anomalies, learning disabilities, postaxial polydactyly, retinal dystrophy, obesity, and hypogonadism. BBS is a heterogeneous syndrome, both genetically and clinically. To date, genetic variants in more than 28 genes have been associated with this syndrome and its subtypes. Most previous studies on BBS have failed to show clear genotype–phenotype correlations. In order to investigate the spectrum of genetic variation among Iranian BBS patients, 9 subjects from 9 different families with clinically diagnosed BBS were included in this study. Following informed consent, we applied exome sequencing (ES) to the proband and their parents. We next performed Sanger sequencing to validate the identified variants. ES successfully detected four known variants: two in the BBS9 gene, c.2014C > T (p.Gln672Ter) and c.1789 + 1 G > A, one variant in the BBS10 gene (c.728_731del; p.Lys243Ilefs*15), and one variant in the MKKS gene (c.515_516del; p.Glu172Alafs*19). ES also detected two new variants in the BBS7 gene, c.880G > C (p.Gly294Arg) and c.719G > A (p.Gly240Asp), one new variant in the CEP290 gene, c.5159C > G (p.Thr1720Arg), and one new variant, in the TTC8 gene, c.462_465del (p.Ser155Glufs*20). In addition, ES identified one novel homozygous deletion of exon 16 in the BBS9 gene. Among the clinical manifestations observed, obesity and polydactyly were the most common findings. Our findings further support the high heterogeneity of BBS: by discovering known, new, and novel pathogenic variants. We expand the mutational spectrum of BBS-related genes and contribute to the understanding of this multisystem disease.

Gangliosidosis is a hereditary metabolic disorder inherited in an autosomal recessive manner. This disorder is marked by the accumulation of gangliosides in the central nervous system, leading to considerable and progressive neurological deficits. In the current study, we described the clinical findings and genetic variations observed in 12 patients manifesting symptoms of gangliosidosis disorders. The results of molecular investigations revealed the presence of different variants in the HEXA (three cases), HEXB (four cases) and GLB1 genes (five cases) in the patients. Notably, the c.833C > T (p.A278V) variant in the HEXB was detected in two unrelated cases. Four novel variants were also detected, including two likely pathogenic variants in the HEXB gene, namely c.1083-2del and c.1616_1622dup (p.Ile541Metfs*14). A single case had three variants in the GLB1 gene, including two novel variants (c.545C > T and c.631G > C); and a previously reported pathogenic variant (c.601C > T). The current study broadens the spectrum of genetic variations in Iranian patients with different types of gangliosidosis. This information is also important for the process of genetic counseling in the affected families.

Peroxisomal disorders are a group of hereditary metabolic disorders that happen when peroxisomes are defective. Around 80% of individuals affected by peroxisomal disorders are classified within the spectrum of Zellweger syndromes with autosomal recessive inheritance pattern that results from mutations in one of the 13 PEX genes. Clinical exome sequencing plays a vital role in the diagnosis where the symptoms are atypical. In the current study, we used this technique to find the underlying genetic cause in 14 Iranian patients with peroxisomal disorders. PEX1 variants were detected in five patients. PEX2, PEX5, PEX6 and PEX7 variants were detected in three, one, one, and two cases, respectively. Finally, ACOX1 variants were identified in two cases. All cases except two cases were homozygote for the suspected variants in Zellweger syndrome-related genes. Two cases were compound heterozygote for variants in the PEX1 gene. In total, two novel variants were identified, including c.313 C > T (p.Gln105*) and c.961 A > T (p.Ile321Phe) in the PEX1 and ACOX1 genes, respectively. The present research expands the range of genetic variations observed in Iranian individuals diagnosed with various forms of Zellweger spectrum disorders.

Biallelic NDUFA9 variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of NDUFA9-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of NDUFA9-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic NDUFA9 variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new NDUFA9 variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic NDUFA9 variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.

Copper is indispensable for various metabolic processes, notably mitochondrial respiration. In humans, copper homeostasis hinges on transporters such as copper transporter 1 (CTR1), encoded by the SLC31A1 gene. Recently, bi-allelic mutations in SLC31A1 have been associated with a new neurodevelopmental disorder. This study presents clinical, genetic, and biochemical findings from 13 new cases across 10 families worldwide. RNA sequencing evaluated gene expression, and Western blotting assessed copper transporter 1 protein levels. Additionally, mitochondrial respiratory capacity was measured via high-resolution respirometry. Affected individuals exhibited a distinct clinical phenotype characterized by early-onset epileptic encephalopathy, severe neurodevelopmental delay and hypotonia, with high mortality. Neuroimaging revealed significant brain atrophy and white matter abnormalities. Genetic analysis identified bi-allelic SLC31A1 variants, predominantly p.His120Gln in six cases and p.(Arg102Cys/His) in three cases. Functional studies in patient fibroblasts demonstrated impaired mitochondrial respiration. This study significantly broadens the clinical spectrum of this recently described syndrome, presenting as a severe developmental encephalopathy with high mortality risk, and suggests mitochondrial dysfunction as a potential pathomechanism. These findings contribute to the mounting evidence linking copper transporter 1 dysfunction to neurodegeneration, underscoring the urgency for further therapeutic investigations.

Background and purpose: Diabetic nephropathy (DN) is a major microvascular complication of type 2 diabetes mellitus (T2DM) that can lead to kidney failure. In this study, the expressions of the lncRNA HOTAIR and PVT1 genes were investigated in individuals with type 2 diabetes with DN, individuals with type 2 diabetes without DN, pre-diabetic individuals, and healthy controls. The study also examined the expression levels of lncRNA HOTAIR and PVT1 in HEK-293 cells treated with high glucose (HG) and normal glucose (NG). Materials and methods: In this cross-sectional study, the expression levels of the lncRNA HOTAIR and PVT1 genes were compared among four groups: 50 healthy individuals, 50 individuals with prediabetes, 50 patients with T2DM, and 50 patients with DN. To model DN in vitro, HEK-293 cells were cultured under high-glucose (HG; 100 mmol/L) and normal-glucose (NG) conditions for 72 hours, and the expression levels of HOTAIR and PVT1 were measured in the treated cells. Results: The current work showed that the expression level of lncRNA PVT1 was significantly increased in individuals with DN compared with the healthy and prediabetic groups, but there was no significant difference when compared with the T2DM group. The analysis also indicated that the expression level of lncRNA HOTAIR was elevated in the DN group compared with the other groups. Under high-glucose (HG) conditions, an increase in lncRNA PVT1 expression was observed, while no change was detected in the expression level of lncRNA HOTAIR. Conclusion: The results of this study suggest that lncRNA HOTAIR and lncRNA PVT1 play roles in the pathogenesis of DN, with lncRNA PVT1 showing a stronger association with glucose-induced cellular changes than lncRNA HOTAIR