Inborn errors of immunity (IEI) refer to a heterogeneous group of monogenic disorders caused by germline variants that disrupt immune function. Among these conditions, immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene. c Rel is a key actor of the NF-κB pathway with major implications in the immune response. Up untill now, only two patients with confirmed pathogenic REL variants have been reported. Here, a third case is described of a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections, alongside newly reported features including craniosynostosis, language delay, and epilepsy. Clinical exome sequencing, confirmed by Sanger sequencing, identified a novel homozygous frameshift variant (NM_001291746.4) REL:c.24del p.(Tyr9Ilefs*2). This variant introduces a very early premature stop codon. Western blot analysis of peripheral blood mononuclear cells demonstrated a severe reduction of c Rel protein expression with preserved p65 levels, confirming its functional impact. This report expands the mutational spectrum of REL and further supports the critical, non-redundant role of c-Rel in human immune homeostasis. It also highlights the central role of next generation sequencing, particularly clinical exome approaches, in the diagnosis and evolving genetic classification of IEI, enabling earlier recognition, refined subclassification, and more personalized management of affected patients.

Previous studies have highlighted significant genetic structure among Southeast Asian populations, with Northern Borneo natives closely related to Austronesians from Taiwan and the Philippines, and Peninsular Malaysia indigenous populations potentially linked to the indigenous Andamanese. In this study, we analyzed 96 genomes from indigenous populations in Peninsular Malaysia, genotyped with approximately 2 million genome-wide autosomal SNPs, alongside datasets from Singapore cosmopolitan Malays and five native populations from Sabah, Northern Borneo. Our findings reveal distinct genetic structures between indigenous populations and Malays, despite their shared habitat. The Malays exhibit substantial admixture with East Asian, Austronesian, and indigenous Peninsular Malaysian ancestral components. Indigenous populations showed lower within-population diversity and longer linkage disequilibrium compared to benchmark populations. Estimated divergence times suggest that the Semang represent an earlier branching population (∼10,000 years ago), followed by Northern Borneo natives (∼7,600-6,H800 years ago), with Malays diverging more recently. These results support a scenario of successive migration waves into Southeast Asia, providing insights into the genetic history and population structure of the region.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

This study aimed to determine the prevalence of Duffy, HbS, HbC, G6PD, and β-thalassemia variants through molecular characterisation in a representative sample of the population from the urban area of Buenaventura, Colombia. A total of 819 individuals were randomly selected from 12 communities within the city. Molecular analysis was performed using PCR-RFLP and allele-specific PCR. Data were analysed using descriptive statistics, tests of independence, and regression analysis. Frequencies of 3.1%, 2.2%, 72.2%, 2.1%, 2.8%, and 11% were found for the resistance alleles HbS, HbC, Duffy, β-thalassemia-29, β-thalassemia-88 and G6PD, respectively. In addition, adolescents and young adults (13 to 26 years) presented the highest proportion of resistance genotypes. Likewise, the communities of the insular zone of Buenaventura had the highest proportion of resistance genotypes. These findings should be considered by public health and disease prevention authorities, as they highlight specific age groups and communities that may be more susceptible to malaria infection. They also identify groups that may contribute to the persistence and potential increase in the prevalence of haemoglobinopathies in the population over time.

The aim of this systematic review is to identify all genome-wide association study (GWAS)-based polygenic risk score (PRS) studies (with different PRS approaches) reported in African ancestry populations diagnosed with any type of cancer. Additionally, this review assessed the role of PRS in advancing precision medicine through its clinical utility across different cancer types in African populations. We searched PubMed from January 2009 to April 2023 and included GWAS-based PRS studies for cancer patients of African genetic ancestry. Among the 33 eligible studies, prostate cancer and breast cancer were the most common types in adults, whereas only one publication reported the risk association of neuroblastoma (a pediatric cancer). The most common PRS approach used was ancestry-specific PRS. Clinical utility of the calculated PRS varies across cancer types, with inconsistent results. Our systematic review found a limited number of PRS studies on cancer patients (adult and pediatric) of African ancestry, and these studies showed less clinical utility compared to those conducted in European ancestry populations. To make PRS clinically actionable for African ancestry populations, it is crucial to increase the number of large-scale, population-specific GWAS, improve the representation of African-ancestry cohorts, and refine PRS models to better reflect the genetic diversity within African populations.

Alzheimer's disease (AD) predominantly affects older women, with research suggesting elevated follicle-stimulating hormone (FSH) levels in postmenopausal women correlate with AD risk and cognitive decline. Understanding the causal relationship between FSH and AD is essential. We selected single-nucleotide polymorphisms (SNPs) linked to FSH as instrumental variables (IVs) for Mendelian randomization (MR). Statistical methods, including inverse variance weighted (IVW), MR Egger, Weighted Median, Weighted Mode, and Simple Mode, were employed to assess causality and potential pleiotropy. Shared genetic loci between FSH and AD were explored. We carefully identified and utilized a total of 20 valid SNPs as IVs to assess the potential causal relationship between FSH and AD. Our analysis revealed a significant causal association between genetically determined FSH levels and AD [beta=-0.004; OR=0.996, 95% confident interval (CI): 0.994-0.999; p=0.002]. We successfully identified 20 SNPs that correspond to 8 differentially expressed genes (DEGs) between AD and non-demented (ND). These genes have not been previously reported to be linked to either FSH or AD. We conducted an in-depth analysis to explore the potential roles of these genes in the context of FSH and AD. Our MR study revealed that FSH potentially has a causal association with AD. Additionally, FSH might possess distinctive biological mechanisms that influence the development of AD.

In recent years, numerous genetic variants have been linked with prelingual hearing loss (HL). Variants in the LOXHD1 gene (lipoxygenase homology domain-1) associated with DFNB77 are highly heterogeneous, with different auditory characteristics varying from stable to progressive and mild to profound. To date, 168 DFNB77 cases have been recorded worldwide. Forty-one hearing-impaired (HI) probands, who were previously excluded for a set of four common deafness-causing genes (viz., GJB2, GJB6, SLC26A4, and CDH23) from 33 HI families, were subjected to clinical exome sequencing (CES) involving 285 genes associated with HL. This was followed by a segregation analysis of the available members in the family. We identified two pathogenic LOXHD1 variants in two unrelated inbred families. One is a novel homozygous pathogenic nonsense variant (c.3999C>A; p.C1333X), whereas the other is a likely pathogenic missense variant (c.6046G>T; p.E2046K). In silico tools such as SIFT, PolyPhen-2, Mutation Taster, CADD, and REVEL scores were used to predict variant pathogenicity. Furthermore, American College of Medical Genetics and Genomics guidelines specific to HL were applied to finally classify a variant as pathogenic or otherwise. The frequency of LOXHD1 variants identified in our study is 4.88% (2/41). This is the first LOXHD1 report associated with non-syndromic HL in South Indian families.

Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine-threonine kinase domain 2 (FASTKD2) (MIM# 612322). COXPD44 is characterized by variable clinical features-developmental delay, chronic epileptic encephalopathy, seizure disorder/status epilepticus and cerebellar ataxia. We ascertained one sibwith episodic acute encephalomyopathy triggered by acute gastroenteritis and associated with haematological abnormalities, rhabdomyolysis leading to acute kidney injury, hypotensive shock leading to early death and a similarly affected sib with early death. Both siblings were normal neurologically in between the acute episodes. Whole exome sequencing (WES) was performed in the elder sibling. Mitochondrial respiratory chain enzyme activity assaywas performed in fibroblast cells and muscle tissue of the elder sibling. Also, Adenosine triphosphate (ATP) determination assay was done in fibroblast cells of the elder sibling. WES revealed compound heterozygous missense likely pathogenic variants in FASTKD2. Mitochondrial respiratory chain enzyme activity in muscle tissue showed reduced complex IV activity and ATP determination assay showed a reduction of ATP in skin fibroblasts. Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in FASTKD2 associated with the variable phenotypes and mitochondrial OXPHOS defect.