Clinical Genetics最新文献

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).

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.

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.

This study investigated genetic causes of 46, XY DSD in 134 Chinese patients via whole-exome sequencing (WES). Clinical data analysis identified 86 rare variants (14 novel, 72 recurrent) across 46, XY DSD-related genes. Following ACMG guidelines, 71 variants were classified as pathogenic/likely pathogenic (P/LP). Affected genes were linked to androgen production/function (63 variants), testicular development (19), and syndromic forms (4). SRD5A2, AR, and NR5A1 emerged as the most frequent causative genes, accounting for ~90% of cases. Novel variants in 11 genes expanded the genetic spectrum, offering insights into underlying mechanisms and improving diagnostic precision. These findings enhance understanding of 46, XY DSD pathogenesis and underscore WES's utility in resolving diagnostic challenges for improved clinical management.