Biallelic pathogenic expansions in RFC1 contribute to the genetic etiology of PD, with a frequency similar to that of other known autosomal recessive PD genes. RFC1-positive PD is currently not clinically distinguishable from RFC1-negative PD, but genetic background may play a role in future therapies or other interventions.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene. Existing toxin-induced and genetic models provide important insights, but none fully replicate the progressive pathology of HD. An AAV9-mediated striatal mouse model expressing mutant HTT with 82 CAG repeats was established to reproduce hallmark neuropathological changes and behavioral deficits. Male C57BL/6 mice received bilateral intrastriatal injections of AAV9-HTT-82Q or control AAV9-GFP. Behavioral performance was assessed by rotarod, balance beam, open field, and Y-maze tests. Neuropathology was examined with HE/Nissl staining, TUNEL assay, and immunofluorescence for mHTT, DARPP-32, GFAP, and Iba1. AAV9-82Q mice exhibited progressive motor coordination deficits on the rotarod from Week 4 and impaired beam traversal from Week 18. Open field testing revealed persistent hyperactivity from Week 8, while anxiety-like and cognitive measures showed only mild, non-significant trends. Histological analysis demonstrated extensive mHTT aggregation in the striatum, accompanied by neuronal pyknosis, vacuolization, and significant loss of Nissl-positive neurons. TUNEL staining confirmed increased apoptosis. Immunofluorescence further revealed selective reduction of DARPP-32+ medium spiny neurons, along with marked astrogliosis and microgliosis, indicating robust neurodegeneration and inflammatory responses. The AAV9-82Q model induces adult-onset, progressive HD-like pathology with early motor impairments, neuronal loss, and glial activation. It complements existing models and provides a reproducible platform for mechanistic studies and preclinical therapeutic evaluation.
De novo CCNK missense variant associated with mild intellectual disability, subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), and ventriculomegaly. This case broadens the clinical spectrum of CCNK-related neurodevelopmental disease and supports cyclin K as a disease gene; imaging and phenotype suggest a milder presentation compared with deletions.
This systematic review and meta-analysis assesses the distribution and health implications of apolipoprotein E (ApoE) ε2, ε3, and ε4 alleles, which play crucial roles in lipoprotein metabolism, in South Asian populations, with a focus on neurodegenerative diseases, movement disorders, traumatic brain injury, mental health disorders, cardiovascular disorders, metabolic disorders, and trauma-related disorders. A total of 53 studies identified through comprehensive searches in PubMed, Embase, and Google Scholar up to July 31, 2024, were included on the basis of predefined eligibility criteria after Risk of Bias Assessment via the New York Ottawa Scale. ε3/ε3 was found to be the most prevalent genotype, followed by ε3/ε4 and ε2/ε3. ε4-containing genotypes were associated with susceptibility to Alzheimer's disease, coronary artery disease, vascular dementia, and obesity, though high heterogeneity in some associations necessitates cautious interpretation, whereas the ε2/ε3 and ε2 alleles showed protective effects in some conditions. These studies had several limitations, including data gaps for specific health conditions, underrepresentation of some South Asian countries, and heterogeneity in outcomes. Despite gaps in the data for some countries and specific health conditions, this review reveals distinct South Asian patterns in ApoE polymorphism–disease associations, highlighting the need for targeted genetic research and tailored public health strategies to advance personalized medicine and healthcare policies in this region. There was no specific funding for this study. The study was registered in PROSPERO (registration number CRD42024575197).
Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis, and upper airway obstruction, often occurring with cleft palate and syndromic conditions. The genetic basis of RS is heterogeneous, including monogenic variants and chromosomal rearrangements. This systematic review synthesizes the current genetic landscape of RS, analyzing data from 107 studies that employed various genetic testing methods, including chromosomal microarray (CMA), targeted sequencing, and whole exome sequencing (WES). A distinction is made between genetic variants identified in isolated versus non-isolated RS. Pathogenic variants in genes as SOX9, SNRPB, SATB2, TGDS, RBM10, COL11A1, and COL2A1 are frequently identified, many of which are linked to non-isolated RS. The most common chromosomal aberrations are deletions of 22q11.2 and 18q. Up-to-date genetic testing is essential to enable accurate diagnosis and personalized clinical care. With the growing use of whole genome sequencing (WGS) in clinical practice, the need for phenotype-driven interpretation tools is increasing. Some platforms can prioritize gene relevance based on Human Phenotype Ontology (HPO) terms. Documenting both known and novel RS-associated genes is therefore crucial to fully realize the diagnostic potential of WGS and support evidence-based clinical decision-making.
Founder variants—disease-causing genetic variants inherited from a common ancestor—have been extensively documented in isolated populations, shedding light on population history, disease prevalence, and genetic drift. In the context of the Turkish population, which lies at the crossroads of Europe and Asia and has experienced a complex demographic history including migration, admixture, a significant number of founder variants have been identified in Türkiye as well as other countries hosting Turkish people. These variants are mostly associated with autosomal recessive disorders and are particularly enriched in subpopulations with high rates of consanguinity. This review aims to compile known founder variations in the Turkish population based on published literature, interpret their historical origins in light of Anatolian population dynamics, and discuss the implications of these variants for genetic counseling, disease gene discovery, and precision medicine. Understanding founder effects in the Turkish population not only provides insight into the nation's population genetics but also supports broader investigations into rare diseases in Middle Eastern and Euro-Asian populations.
Advances in next-generation sequencing (NGS) have revolutionized clinical and translational medicine. NGS is increasingly used in the diagnosis of genetic diseases, including newborn screening, prenatal screening and diagnosis, and preimplantation screening. While advancements in sequencing and bioinformatics have facilitated the discovery of novel genes and diseases, the identification of variants continues to outpace our ability to classify them accurately. Variants of uncertain significance (VUS), defined as genetic alterations with insufficient evidence for clinical interpretation, present significant diagnostic challenges. Clinically available functional studies, such as biochemical testing, offer valuable insights for interpreting VUS. This review synthesizes recent literature on amniotic fluid metabolite analysis for prenatal diagnosis and VUS interpretation in four organic acidurias. It aims to guide the application of biochemical testing for inherited metabolic disorders and enhance clinical decision-making regarding VUS classification.
Dilated Cardiomyopathy (DCM) is a genetically heterogeneous condition of left ventricular dilation and systolic dysfunction, leading to heart failure. It is mostly inherited in a dominant pattern. Recessive inheritance has been rarely encountered. This study aims to outline the clinical and genetic characteristics associated with recessively inherited NRAP truncating variants in our highly consanguineous population. Twenty-three cases from 12 unrelated consanguineous families were recruited. Cardiological evaluation and genetic testing with exome sequencing (ES) were conducted in all cases, followed by segregation analysis of first-degree relatives. Genetic analysis with ES identified five unique homozygous truncating variants in NRAP in the affected cases. The segregation analysis detected a total of 23 homozygous and 21 heterozygous individuals. Out of the total homozygous cases, three were asymptomatic, while 20 exhibited symptoms with remarkable inter- and intrafamilial variability of the age of onset (range: 9 months to 47 years, median 10 years), seven of whom died (range: 9 months to 28 years, median 7 years). None of the heterozygous individuals showed symptoms. Of note, three homozygous cases underwent heart transplantation. Our findings show that truncating variants in NRAP are associated with reduced penetrance and clinical variability, suggesting a complex mechanism beyond simple Mendelian inheritance.
The nexin–dynein regulatory complex (N-DRC) is a large protein complex composed of at least 11 subunits (DRC1–DRC11) and plays a crucial role in ciliary and flagellar motility. It links adjacent doublets of microtubules (DMTs) between A and B microtubules, regulating dynein motor activity. Genetic defects in N-DRC subunits lead to primary ciliary dyskinesia (PCD) and abnormal flagellar motility. In recent years, an increasing number of genetic mutations in N-DRC subunits have been reported, associated with male infertility, characterized by multiple morphological abnormalities of the flagella (MMAF) and asthenozoospermia. Therefore, genetic diagnosis of N-DRC defects in male infertility is of significant clinical importance, impacting the reproductive health of patients and the well-being of their offspring. In this review, we summarize the gene mutations of N-DRC subunits reported in the literature concerning male infertility, analyze the phenotypes of affected patients, and outline the functions and mechanisms of N-DRC in sperm flagellar motility. Furthermore, we provide an overview of gene knockout (KO) mouse models of N-DRC and their associated phenotypes. Finally, we summarize the outcomes of assisted reproductive technology (ART) in both patients and KO mice, offering references for the diagnosis and treatment of clinical male infertility caused by N-DRC genetic factors.
Fanconi anemia (FA) is a multiorgan disease caused by pathogenic variants in genes involved in the FA/BRCA DNA repair pathway. We report a 10-year-old female who presented with multiple congenital anomalies consistent with VACTERL (Vertebral anomalies, Anal atresia, Cardiac anomalies, Tracheoesophageal fistula, Esophageal/duodenal atresia, and Renal and Limb anomalies) and PHENOS (abnormal Pigmentation, small Head, small Eyes, central Nervous system anomalies, Otological anomalies, short Stature), and later exhibited global developmental delay. She tested positive for a de novo likely pathogenic variant in RAD51 and had inconclusive chromosomal breakage studies. This case provides evidence for a common association between RAD51-related FA and VACTERL and expands its genotypic and phenotypic spectra.
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