Search Results (95)

Hemolytic anemias (HAs) encompasses a heterogeneous group of disorders with either congenital or acquired etiologies. We present a complex case of a 27-year-old woman with hemolytic anemia of multifactorial origin, involving both inherited RBC membrane defects and multiple autoimmune comorbidities. Genetic testing identified heterozygous variants in SPTA1 and SBDS, consistent with carrier status for hereditary elliptocytosis and Shwachman–Diamond syndrome. The patient was also diagnosed with Caspr2-positive Isaacs syndrome, systemic lupus erythematosus, seronegative antiphospholipid syndrome, and anti-aquaporin-4 antibody-positive optic neuritis. Despite extensive immunosuppressive and immunotherapic treatment and splenectomy, the clinical course was marked by recurrent hemolytic crises, thrombotic complications, and progressive neurological involvement, ultimately leading to death. Our experience highlights the challenges posed by the diagnosis and management of HAs, underlining the relevance of a multidisciplinary and personalized approach. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare hereditary disorder caused by defective motile cilia, predominantly affecting the respiratory system. Conductive hearing loss (CHL) due to chronic otitis media with effusion (OME) is a typical feature of PCD, particularly in childhood. However, the underlying mechanisms contributing to sensorineural hearing loss (SNHL) in patients with PCD remain unclear. Methods: We present the case of a 52-year-old male with a clinical diagnosis of PCD, confirmed by the presence of situs inversus, chronic respiratory symptoms, and ultrastructural ciliary defects. Results: Despite a history of recurrent acute otitis media (AOM), the patient developed severe bilateral SNHL, a relatively uncommon and poorly understood manifestation of PCD. Genetic testing revealed a pathogenic SH3TC2 variant, a gene classically associated with Charcot–Marie–Tooth disease type 4C (CMT4C), raising the possibility of an alternative or contributory genetic etiology for the patient’s auditory dysfunction. Conclusions: This case highlights the importance of comprehensive audiological and genetic evaluations in PCD patients, particularly those presenting with progressive or atypical HL. The presence of a pathogenic SH3TC2 mutation suggests a potential neuropathic component to the patient’s HL, underscoring the need for further research into the intersection between ciliary dysfunction and genetic neuropathies. Early identification and intervention are critical to optimizing auditory outcomes and quality of life in affected individuals. Full article

Anderson Fabry disease (AFD) is an X-linked hereditary lysosomal abnormality that causes the accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and a shortened life span. More than 1000 mutations in the GLA gene have been identified, promoting many different clinical pictures. For this reason, diagnosing AFD can be difficult, especially because of the great diversity of atypical clinical presentations that can simulate the disease. Some of these variants of the GLA gene have been described as non-pathogenic. For example, the D313Y variant is one of the most controversial, even if there are several case reports of D313Y patients presenting with signs and symptoms consistent with AFD without any other etiological explanation. This work aimed to clarify whether the presence of the D313Y variant affects α-Gal A activity and causes AFD symptoms and organ involvement in two patients from different families. The presence of the D313Y variant resulted in clinical manifestations of AFD in both patients and a decrease in alpha-galactosidase activity in the male patient. Two patients (one female and one male) from two unrelated families were examined. Sequencing of all seven GLA exons and the adjacent 5′ and 3′ exon–intron boundaries identified the D313Y variant in exon 6, as well as the genetic variation g.1170C>T in the flanking 5′ UTR in patient 1 only. Our results suggest that the D313Y variant is causative for the disease and that the clinical phenotype can be enhanced by the presence of other variants modulating protein expression. Full article

Background/Objectives: Hypermobile Ehlers–Danlos syndrome (hEDS) is the most common subtype of Ehlers–Danlos syndromes (EDS), a heterogeneous group of hereditary connective tissue disorders. The hallmark features of hEDS include generalized joint hypermobility (GJH), soft or velvety skin, and persistent joint pain. The molecular etiology of hEDS remains unknown, and diagnosis is primarily clinical. The updated diagnostic criteria for hEDS requires the fulfillment of three criteria: (1) GJH, (2) a combination of musculoskeletal and systemic manifestations consistent with a connective tissue disorder, and (3) the exclusion of alternative diagnoses. However, the exclusion process and the role of genetic testing have not yet been fully refined. Methods: This retrospective review utilized data from the Hereditary Connective Tissue Disorders (HCTD) patient registry at the University of Miami, which includes individuals evaluated at the HCTD Clinic using a standardized internal clinical and genetic protocol. We analyzed data from 907 patients referred for hEDS evaluation between June 2019 and December 2022. Results: Among these patients, 178 met the 2017 diagnostic criteria for hEDS. Genetic testing identified an alternative or additional diagnosis in 47 of these individuals (26.4%), with clinical implications requiring distinct management strategies. Conclusions: These findings underscore the importance of criterion three—exclusion of alternative diagnoses—and highlight the critical yet underutilized role of genetic testing in the assessment of joint hypermobility. Furthermore, the results suggest that hypermobility may present a shared phenotype across a spectrum of disorders, including inflammatory diseases, monogenic syndromes, and chromosomal abnormalities. Full article

Background: Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) enables more accurate evaluation of underlying etiologies. The existing clinical evidence regarding genetic testing in adults with NL comprises only a few cohort studies. Materials and Methods: We retrospectively analyzed 49 adult patients diagnosed with NL and/or NC from a single center, on whom we performed a genetic test using a nephrolithiasis panel. We reviewed the phenotype of the patients and compared the cases with positive and negative molecular diagnosis. Results: In total, 49 adult patients with NL and/or NC underwent genetic testing. Of the tested patients, 29 (59.2%) patients had 24 abnormal variants in 14 genes. Mendelian diseases were diagnosed in 14 (28.6%) cases: cystinuria (SLC3A1, SLC7A9; n = 4), hereditary distal renal tubular acidosis (SLC4A1; n = 3), Dent disease (CLCN5; n = 2), familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (CLDN16; n = 1), infantile hypercalcemia type 1 (CYP24A1; n = 1), primary hyperoxaluria type 1 (AGXT; n = 1), Bartter syndrome type 2 (KCNJ1; n = 1), and autosomal dominant tubulointerstitial kidney disease (UMOD; n = 1). Eight (16.3%) patients had pathogenic or likely pathogenic monoallelic variants as predisposing factors for NL and/or NC, and seven (14.3%) had biallelic or monoallelic variants of uncertain significance. Patients with positive genetic tests had a lower estimated glomerular filtration rate (p = 0.03) and more frequent NL associated with NC (p = 0.007) and were unlikely to have arterial hypertension (p = 0.03) when compared with patients with negative tests. Conclusions: Our study shows an increased effectiveness of molecular diagnosis and highlights the benefits of genetic testing. NL associated with NC and the presence of chronic kidney disease are the characteristics that should prompt the clinician to suspect an inherited form of NL and/or NC. Full article

Background: As a complicated endocrine condition, polycystic ovarian syndrome affects around 20% of women who are of reproductive age. It is linked to an increased risk of endometrial cancer, cardiovascular diseases, mental illnesses, non-alcoholic fatty liver disease, metabolic syndrome, and Type 2 diabetes. Despite numerous genetic studies identifying several susceptibility loci, these only account for approximately 10% of the hereditary factors contributing to PCOS, leaving its etiology largely unknown. While genome-wide association studies (GWAS) have been conducted on various populations to identify SNPs linked to PCOS risk, no such study has been reported in Tabuk. Thus, this study aims to investigate the association of a glutathione S-transferase M1 (GSTM1) deletion, VEGF gene (I/D) insertion/deletion, and VEGF-2578 gene polymorphism with polycystic ovarian syndrome. Methodology: In this research study (case-control), we utilized the ARMS-PCR to determine and analyze the polymorphic variants of VEGF-2578 C/A (rs699947). We employed multiplex PCR for the GSTM1 deletion and MS-PCR (mutation specific PCR) for the vascular endothelial growth factor gene insertion/deletion. Results: The findings indicated statistically significant differences in various biochemical and endocrine serum biomarkers, including lipid profiles (cholesterol, HDL, and LDL), Type 2 diabetes markers (HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), free insulin fasting glucose), and hormone levels (testosterone, LH, progesterone and FSH) in PCOS patients. Specifically, regarding the GSTT1 genotype, individuals with the GSTT1-null genotype had an odds ratio (OR) of 4.16 and a relative risk (RR) of 2.14 compared to those with the GSTT1 genotype, with statistically significant differences (p = 0.0001). However, for the GSTM1 genotype, there was a statistically significant difference (p = 0.0002) in the OR and RR for the GSTM1-null genotype, which were 2.66 and 1.64, respectively. Protective effects were observed for individuals with either GSTT1 (+) GSTM1 (−) or GSTT1 (−) GSTM1 (+) genotypes, as well as for those with both null genotypes, yielding an OR of 0.41 and p < 0.003. The VEGF rs699947 C>A gene variation showed a statistically significant association between PCOS patients and controls (p < 0.020), with the A allele frequency higher among PCOS patients (0.42 vs. 0.30). Similarly, the VEGF rs4646994 I>D gene variation exhibited a statistically significant difference (p < 0.0034), with the D allele being more frequent in PCOS patients (0.52 vs. 0.35). The VEGF-A allele was strongly linked to PCOS susceptibility in the allelic model, exhibiting an OR of 1.62, RR of 1.27, and p < 0.007, while in the allelic comparison, the OR was 1.71, the RR was 1.32, and p < 0.004. Conclusions: This study concluded that null genotypes at rs4025935 and rs71748309, an insertion deletion at rs4646994, and the A allele of rs699947 were significantly associated with PCOS predisposition in our population and these could serve as potential loci for PCOS predisposition. To the best of our knowledge, it is the first study to highlight the association between these genetic variations and the predisposition of PCOS in our populations. Large-scale case-control studies in the future are required to confirm these results. Full article

Hypermobile Ehlers–Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and systemic manifestations such as chronic fatigue, gastrointestinal dysfunction, and neurological symptoms. Unlike other EDS subtypes with known genetic mutations, hEDS lacks definitive markers, suggesting a multifactorial etiology involving both mitochondrial dysfunction and non-mitochondrial pathways. This scoping review, conducted in accordance with the PRISMA-ScR guidelines, highlights mitochondrial dysfunction as a potential unifying mechanism in hEDS pathophysiology. Impaired oxidative phosphorylation (OXPHOS), elevated reactive oxygen species (ROS) levels, and calcium dysregulation disrupt cellular energetics and extracellular matrix (ECM) homeostasis, contributing to the hallmark features of hEDS. We reviewed candidate genes associated with ECM remodeling, signaling pathways, and immune regulation. Protein–protein interaction (PPI) network analyses revealed interconnected pathways linking mitochondrial dysfunction with these candidate genes. Comparative insights from Fabry disease and fragile X premutation carriers underscore shared mechanisms such as RNA toxicity, matrix metalloproteinases (MMP) activation, and ECM degradation. These findings may suggest that mitochondrial dysfunction amplifies systemic manifestations through its interplay with non-mitochondrial molecular pathways. By integrating these perspectives, this review provides a potential framework for understanding hEDS pathogenesis while highlighting latent avenues for future research into its molecular basis. Understanding the potential role of mitochondrial dysfunction in hEDS not only sheds light on its complex molecular etiology but also opens new paths for targeted interventions. Full article

Background: Hereditary Sensory Motor Neuropathy (HSMN) 1A and Multiple Sclerosis (MS) are distinct demyelinating disorders affecting the peripheral and central nervous systems, respectively. We present a case of simultaneous occurrence of both conditions, exploring the clinical presentation, diagnostic workup, and potential interplay between these diseases. Case presentation and clinical approach: A 49-year-old male with a history of optic neuritis presented with progressive numbness, weakness, and sensory loss in all extremities over four years. Neurological examination revealed distal weakness, sensory deficits in a stocking-glove distribution, pes cavus, and hammer toes. Nerve conduction studies and electromyography confirmed sensory motor demyelinating polyneuropathy. The patient’s lack of response to intravenous immunoglobulin therapy suggested hereditary neuropathy as an etiology. Genetic testing identified a PMP22 gene duplication, confirming HSMN 1A. Elevated cerebrospinal fluid protein level and oligoclonal bands, combined with magnetic resonance of the brain showing multiple T2 hyperintense lesions in the brain and spinal cord, fulfilled the diagnostic criteria for MS. Discussion: This case of co-existing HSMN 1A and MS highlights a rare overlap of peripheral and central demyelination. While HSMN 1A results from PMP22 gene duplication, primarily affecting peripheral myelin, MS is driven by immune-mediated central myelin attacks. The co-existence of these disorders suggests potential shared mechanisms, such as immune dysregulation. Some evidence suggests that overexpression of PMP22 in HSMN 1A may disturb immune tolerance, possibly triggering autoimmune responses linked to MS. Further research is needed to explore the genetic and autoimmune interplay between these two diseases, expanding our understanding of demyelinating disorders. Full article

Objective: Congenital, non-syndromic orofacial clefts (CL/P) are infrequently monogenic in etiology. However, heterozygous pathogenic CDH1 germline variants were reported in a few non-syndromic CL/P families, as well as in one syndromic form of CL/P: the blepharocheilodontic syndrome. CDH1 encodes epithelial cadherin (E-cadherin), and close to 300 different pathogenic CDH1 variants are listed in the ClinVar mutation database. The majority of CDH1 germline variants are implicated in hereditary diffuse gastric cancer (HDGC) susceptibility. The purpose of this study was to classify the CDH1 c.760G>A (p.Asp254Asn) mutation with respect to its resulting phenotype. Methods: Exome sequencing and targeted Sanger sequencing were performed in a family segregating CL/P. A review of pathogenic CDH1 variants in ClinVar and those identified in a PubMed/MEDLINE search was performed. Results: We identified a family with six individuals, who were 35–77 years old (mean 56 years) at their last examination, uniformly affected with bilateral CL/P. The CDH1 c.760G>A variant segregated with CL/P. This variant had been reported in 21 individuals, most often children and young adults, from six families. We determined a significant sex preponderance for this variant regarding CL/P: all 16 male and 5 of 11 female heterozygotes presented with CL/P. Furthermore, none of the heterozygous individuals in seven families reported any gastrointestinal tumors. Conclusions: The recurrent CDH1 c.760G>A mutation confers a high risk for CL/P, with strong male preponderance. This review of 27 mutation carriers, including 3 who were 68, 70, and 77 years of age, indicates that c.760G>A does not confer an increased risk for HDGC. The relevance of differentiating craniofacial from cancer phenotypes in mutation carriers is substantial for precision medicine and for counseling families. Full article

Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta. The diseases have an insidious evolution and can be encountered as an isolated manifestation or can also be associated with systemic, extra-aortic manifestations (syndromic HTADs). Along with the development of molecular testing technologies, important progress has been made in deciphering the heterogeneous etiology of HTADs. The aim of this study is to identify the genetic variants associated with a group of patients who presented clinical signs suggestive of a syndromic form of HTAD. Genetic testing based on next-generation sequencing (NGS) technology was performed using a gene panel (Illumina TruSight Cardio Sequencing Panel) or whole exome sequencing (WES). In the majority of cases (8/10), de novo mutations in the FBN1 gene were detected and correlated with the Marfan syndrome phenotype. In another case, a known mutation in the TGFBR2 gene associated with Loeys–Dietz syndrome was detected. Two other pathogenic heterozygous variants (one de novo and the other a known mutation) in the SLC2A10 gene (compound heterozygous genotype) were identified in a patient diagnosed with arterial tortuosity syndrome (ATORS). We presented the genotype–phenotype correlations, especially related to the clinical evolution, highlighting the particularities of each patient in a family context. We also emphasized the importance of genetic testing and patient monitoring to avoid acute aortic events. Full article

Background/Objectives: Schizophrenia (SZ) is a severe psychiatric disorder characterized by a complex interplay of genetic, developmental, and environmental factors that significantly increase the risk of suicidal ideation (SI) and suicide attempts (SAs). This systematic review synthesizes current research on the developmental predictors of SI in individuals with SZ, aiming to delineate the multifactorial etiology of suicide within this population. Methods: A comprehensive search across Medline, PsycINFO, and EMBASE databases identified 23 eligible studies, emphasizing the varied methodological approaches and the global distribution of research efforts. Results: These studies demonstrate a robust association between early life adversities, particularly childhood trauma such as physical neglect, emotional abuse, and sexual abuse, and the increased prevalence of SI and SAs in SZ. This review also highlights the significant genetic factors associated with the development of suicidality in SZ, raising the possibility that polymorphisms in inflammation-related genes and neurodevelopmental abnormalities may influence susceptibility to SI. Notably, family history of psychiatric conditions may exacerbate the risk of SI through both hereditary and environmental mechanisms. Environmental factors, including socioeconomic status and social support, are also implicated, underscoring the role of broader socio-environmental conditions influencing outcomes. Conclusions: This review supports the integration of biopsychosocial models in understanding SI in SZ, advocating for interventions addressing the complex interplay of risk factors and the need for longitudinal studies to elucidate the dynamic interactions between risk factors over time. This comprehensive understanding is crucial for developing targeted preventive strategies and enhancing the clinical management of SZ, aiming to reduce suicidality in this vulnerable population. Full article

Breast cancer (BC) is the most prominent tumor type among women, accounting for 32% of newly diagnosed cancer cases. BC risk factors include inherited germline pathogenic gene variants and family history of disease. However, the etiology of the disease remains occult in most cases. Therefore, in the absence of high-risk factors, a polygenic basis has been suggested to contribute to susceptibility. This information is utilized to calculate the Polygenic Risk Score (PRS) which is indicative of BC risk. This study aimed to evaluate retrospectively the clinical usefulness of PRS integration in BC risk calculation, utilizing a group of patients who have already been diagnosed with BC. The study comprised 105 breast cancer patients with hereditary genetic analysis results obtained by NGS. The selection included all testing results: high-risk gene-positive, intermediate/low-risk gene-positive, and negative. PRS results were obtained from an external laboratory (Allelica). PRS-based BC risk was computed both with and without considering additional risk factors, including gene status and family history. A significantly different PRS percentile distribution consistent with higher BC risk was observed in our cohort compared to the general population. Higher PRS-based BC risks were detected in younger patients and in those with FH of cancers. Among patients with a pathogenic germline variant detected, reduced PRS values were observed, while the BC risk was mainly determined by a monogenic etiology. Upon comprehensive analysis encompassing FH, gene status, and PRS, it was determined that 41.90% (44/105) of the patients demonstrated an elevated susceptibility for BC. Moreover, 63.63% of the patients with FH of BC and without an inherited pathogenic genetic variant detected showed increased BC risk by incorporating the PRS result. Our results indicate a major utility of PRS calculation in women with FH in the absence of a monogenic etiology detected by NGS. By combining high-risk strategies, such as inherited disease analysis, with low-risk screening strategies, such as FH and PRS, breast cancer risk stratification can be improved. This would facilitate the development of more effective preventive measures and optimize the allocation of healthcare resources. Full article

Genetic or hereditary kidney disease stands as a pivotal cause of chronic kidney disease (CKD). The proliferation and widespread utilization of DNA testing in clinical settings have notably eased the diagnosis of genetic kidney diseases, which were once elusive but are now increasingly identified in cases previously deemed CKD of unknown etiology. However, despite these diagnostic strides, research into disease pathogenesis and novel drug development faces significant hurdles, chiefly due to the dearth of appropriate animal models and the challenges posed by limited patient cohorts in clinical studies. Conversely, the advent and utilization of human-induced pluripotent stem cells (hiPSCs) offer a promising avenue for genetic kidney disease research. Particularly, the development of hiPSC-derived kidney organoid systems presents a novel platform for investigating various forms of genetic kidney diseases. Moreover, the integration of the CRISPR/Cas9 technique into this system holds immense potential for efficient research on genetic kidney diseases. This review aims to explore the applications of in vitro kidney organoids generated from hiPSCs in the study of diverse genetic kidney diseases. Additionally, it will delve into the limitations of this research platform and outline future perspectives for advancing research in this crucial area. Full article

Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 (UCP1) gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into “beige” adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis. Full article

The universal newborn hearing screening (NHS) program was implemented in Russia in 2008 to replace the high-risk newborn hearing screening. More than 95% coverage and significant improvement in early detection and intervention is achieved. Meanwhile, it was shown that current OAE-based hearing screening missed 13% of newborns with genetically ascertained hereditary sensorineural hearing loss (SNHL). The aim of the study is to assess the results of genetic investigation and NHS in a large cohort of Russian children with bilateral SNHL and to study the feasibility of implementation of combined hearing and genetic screening in Russia. Genetic, audiological and NHS data of 1292 pediatric patients with bilateral SNHL born in 2008–2021 were analyzed. GJB2 sequencing was performed for all subjects, 644 patients had pathological GJB2 genotype, 406 of them were homozygous for c.35delG variant. The group of 155 GJB2-negative patients were searched for other SNHL genes, The pathological genotypes were identified at 87 patients. The most frequent genes were STRC (21.8%), USH2A (16.1%), OTOF (8%) and SLC26A4 (6.9%). Children with confirmed genetic etiology passed NHS in 21% of cases. The perspectives of implementation of national comprehensive newborn hearing and genetic screening including whole exome sequencing technologies are discussed. Full article