Primary immunodeficiency diseases (PIDs) are monogenic inborn immune disorders. Of currently listed 555 genetic inborn errors of immunity (IEI) in 10 IUIS categories, PIDs range from life-threatening severe combined immunodeficiency (SCID) to milder antibody deficiencies. PIDs increase mortality risk and demand genetic/immunological testing. In Iran, high consanguinity rates may warrant influence of genetic factors. Diagnostic challenges due to heterogeneity necessitate application of advanced tools like whole exome sequencing (WES). This study was carried out on Eastern Iran’s PIDs and similar approaches should be employed worldwide in populations that are highly consanguineous. This study focused on 99 patients from Eastern Iran clinically diagnosed with PIDs who were referred for genetic evaluations between 2016 and 2025. Genetic analyses involved DNA extraction from blood samples, WES using Illumina platforms, and in-house bioinformatic pipelines for variant identification and classification. Sanger sequencing and co-segregation studies further validated findings. Medical records, family histories, and pedigrees were thoroughly analyzed. Also we have delineated syndromic and non-syndromic PID disorders. The significant findings were as follows: Finding of 47 novel disease-causing variants; High consanguinity rates (76%) correlated with an 82.8% diagnostic yield and a mortality rate of 8% amongst patients. SCID-associated mutations, as the most common discovered PIDs, found in 16 cases; other common disorders were AR LRBA LOF, AR ATM LOF, and AR EPG5 (possibly hypomorphic LOF). Additionally, certain mutations may link to pregnancy loss which may need further functional studies. Around 70% of unresolved cases were syndromic. The most frequently suspected pathogenic variants (n = 5), all novel and in homozygosity with matching phenotype, were noted in EPG5 and linked to Vici syndrome. In highly consanguineous populations, WES may reach a definite or highly probable genetic diagnosis in over 80% of cases, and that some IEIs may be associated with pregnancy loss. The online version contains supplementary material available at 10.1038/s41598-026-35604-4.

Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immune deficits, cardiomyopathy and progressive motor dysfunction. This devastating condition is caused by pathogenic variants in the EPG5 gene, which encodes a regulator of autophagy, leading to the accumulation of toxic intracellular material and widespread cellular dysfunction. Less-severe EPG5 pathogenic variants have recently been linked to rare familial forms of Parkinson's disease, suggesting deficits in EPG5 function drive a range of neurodegenerative disorders. Currently, there are no effective treatments for any disorders associated with pathogenic variants of EPG5. The underlying cellular mechanisms driving the progressive neurological decline in VS remain poorly understood. Previous studies using Epg5 knockout models have demonstrated severe neurological phenotypes; however, these models have not been characterized for molecular and cellular deficits within the central nervous system. Here we report the generation and analysis of novel genetically engineered mice with mutations in Epg5 as models of VS, including a strain harboring a truncating mutation that recapitulates a patient-derived pathogenic variant and a strain with an Epg5 null allele. These novel Epg5 mutant mouse models exhibited partial perinatal lethality. Neurological deficits of surviving were detectable by 6 weeks of age, and worsen over time. Histological analysis revealed widespread expansion of microglia and astrocytes throughout the central nervous system. Transcriptomic profiling of central nervous system tissue revealed robust neuroinflammatory signatures, sharing molecular profiles with disease-associated microglia observed in other models of neurological disease and injury. The analysis of these novel mouse models of VS suggest a critical role for neuroglial activation in the pathogenesis of VS. These novel in vivo models will be an essential platform for preclinical evaluation of therapeutics that target autophagy-related neurodegeneration in congenital disorders of autophagy and EPG5-associated neurodegeneration.

Pathogenic variants in EPG5 have been associated with Vici syndrome (OMIM #242840) characterized by agenesis of the corpus callosum (ACC), cataracts, cardiomyopathy, hypopigmentation, and immunodeficiency as hallmark features. Additional variable features include microcephaly, hypotonia, developmental delay, and growth retardation. Recently, few reports described milder cases with a neurodevelopmental phenotype and less systemic involvement harboring EPG5 variants suggesting a broader clinical spectrum. Herein, we describe seven patients from six unrelated Egyptian families in whom exome sequencing identified six homozygous (five novel and one previously reported) EPG5 variants. Patients presented with global developmental delay, microcephaly, hypotonia, dystonia, and failure to thrive. Seizures were evident in two patients and showed a variable response to antiepileptic drugs. Fair color of hair and skin was noted in four out of seven patients (57%), while cataracts and cardiomyopathy were observed in one patient each (14%). In addition to ACC, cerebellar and pontine hypoplasia, delayed myelination, and ventricular dilatation were evident in all patients. Interestingly, deep fissure in the frontal lobes, extending from the frontal horn to the frontal pole, was documented in six patients and appears to represent a characteristic feature associated with EPG5 variants. Our study highlights the phenotypic variability associated with EPG5 variants and emphasizes the presence of a phenotypic spectrum ranging from the classic severe Vici syndrome to a neurodevelopmental disorder with less systemic manifestations and a longer survival rate.

Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum. We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects. Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes. Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy. ANN NEUROL 2025;98:932-950.

Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5, a key autophagy gene responsible for Vici syndrome, are associated with PD. Whole-exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early-onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole-genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late-onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls. We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD-F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy-lysosome function in cells derived from EPG5-PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α-synuclein in skin tissue from EPG5-PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain. Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025;98:369-385.