Population Allele Frequencies Research Articles

INVOLVEMENT OF HLA-DRB1*11 AND HLA-DRB1*12 ALLELES IN THE OCCURRENCE OF DENGUE FEVER IN BURKINA FASO

Introduction: Dengue has become the world's most common arbovirosis. In some individuals, genetic factors can increase the risk of developing severe dengue fever. Human leukocyte antigen (HLA) genes are one of the most extensively studied gene groups in human disease. The present study investigated HLA DRB1*11 and HLA DRB1*12 polymorphisms in dengue cases and their susceptibilities in the development of dengue in a population in Ouagadougou, Burkina Faso. Methodology: This was a case-control study involving 56 patients with clinically and biologically confirmed dengue fever and 65 others who had never been in contact with DENV, for a total of 121 individuals. A blood sample was taken from each study participant. After extraction of genomic DNA using the salting-out technique, characterisation of carriage of the HLA-DRB1*11 and 1*12 alleles was carried out using multiplex polymerase chain reaction (PCR). The χ² test, odds ratio (OR), and confidence interval (CI) were calculated using SPSS software to estimate associations and assess the level of risk. Results: Allele frequencies in the general population were 64.4% and 62.8% for HLA DRB1*11 and HLA DRB1*12, respectively. The HLA-DRB1*12 allele was present in 28.9% of cases and 33.9% of controls. The HLA-DRB1*11 allele was present in 32.2% of both cases and controls. In this study, no direct association was found between the presence of the HLA-DRB1*11 and HLA-DRB1*12 alleles and the surveillance of dengue infection. Furthermore, the absence of the HLA-DRB1*11 allele was associated with protection against the development of severe disease (OR = 0.03; 95% CI [0.11 - 0.80]; and p = 0.01). Conclusion: No risk of developing severe dengue fever was found in individuals carrying the HLA-DRB1*11 and HLA-DRB 1*12 alleles. However, further study of other HLA alleles involved in the development of severe dengue may provide more information.

Three Fields Allelic Haplotype Frequencies of HLA‐DPA1 and ‐DPB1 Typed by Next Generation Sequencing of 563 Families in Chinese Han Population

ABSTRACTThe present study investigated the HLA‐DPA1 and ‐DPB1 allele and haplotype frequencies in the Chinese Han population. A total of 563 families, which have been typed for the purpose of haematopoietic stem cell transplantation, were included, and three‐field allelic resolution typing of HLA‐DPA1 and ‐DPB1 of all individuals were defined by the next‐generation sequencing method. HLA‐DPA1~DPB1 haplotypes were determined by allele segregation within a nuclear family. A total of 9 HLA‐DPA1 and 39 HLA‐DPB1 alleles, and 62 HLA‐DPA1~DPB1 haplotypes were identified. The three most frequent alleles at HLA‐DPA1 locus are HLA‐DPA1*02:02:02 (46.581%), HLA‐DPA1*01:03:01 (36.456%) and HLA‐DPA1*02:01:01 (12.167%); and the three most frequent HLA‐DPB1 alleles are HLA‐DPB1*05:01:01 (34.014%), HLA‐DPB1*02:01:02 (18.428%) and HLA‐DPB1*04:01:01 (10.124%). The three most frequent haplotypes are HLA‐DPA1*02:02:02~DPB1*05:01:01 (32.327%), HLA‐DPA1*01:03:01 ~ DPB1*02:01:02 (14.654%) and HLA‐DPA1*01:03:01~DPB1*04:01:01 (9.458%). The HLA‐DPA1*02:01~DPB1*02:02 and HLA‐DPA1*04:01~DPB1*05:01 haplotypes appear to be unique in Han Chinese. Strong global linkage disequilibrium (LD) between HLA‐DPA1 and ‐DPB1 was confirmed (D′ = 0.848, Wn = 0.684). Moreover, the haplotype frequencies based on the family study were compared with the frequencies estimated by the expectation–maximisation algorithm, and the equivalent results were obtained except for haplotypes with very low frequencies. Our data provide a solid base for HLA‐DP dimer association studies and useful information for transplantation and disease association studies.

Toll-like receptors polymorphisms and COVID-19: a systematic review.

COVID-19 is a disease caused by SARS-CoV-2. It became a health problem affecting the lives of millions of people. Toll-like receptors are responsible for recognizing viral particles and activating the innate immune system. The genetic factors associated with COVID-19 remain unclear. Thus, this study aims to assess the association between the polymorphism in Toll-like receptors and susceptibility to COVID-19. We searched the electronic databases (Science Direct, PUBMED, Web of Science, and Scopus) for studies assessing the association between Toll-like receptor polymorphisms and susceptibility to COVID-19. The quality of the studies was assessed using the Q-Genie tool. Thirteen studies were included in this systematic review. The studies analyzed polymorphisms in TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9. We used SNP2TFBS bioinformatic analysis to identify the variants influencing transcription factor binding sites. The Ensembl Genome Browser was used to assess the allele and genotype frequencies in different populations. The bioinformatic analysis revealed that the variant rs5743836 of TLR9 affects the transcription factor binding sites NFKB1 and RELA. The genotype frequency of the variants rs3775291, rs3853839, rs3764880 were higher in East Asian population compared to the other populations. The frequency of the rs3775290 variant was higher in East and South Asian populations. The rs179008 variant was higher in the European population, and the rs5743836 was higher in the African population. Toll-like receptors play an important role in COVID-19 susceptibility. Further studies in different populations are necessary to elucidate the role of Toll-like receptors polymorphisms in SARS-CoV-2 infection.

Cardiovascular Disease Pathogenicity Predictor (CVD-PP): A Tissue-Specific In Silico Tool for Discriminating Pathogenicity of Variants of Unknown Significance in Cardiovascular Disease Genes.

Interpretation of variants of uncertain significance (VUSs) remains a challenge in the care of patients with inherited cardiovascular diseases (CVDs); 56% of variants within CVD risk genes are VUS, and machine learning algorithms trained upon large data resources can stratify VUS into higher versus lower probability of contributing to a CVD phenotype. We used ClinVar pathogenic/likely pathogenic and benign/likely benign variants from 47 CVD genes to build a predictive model of variant pathogenicity utilizing measures of evolutionary constraint, deleteriousness, splicogenicity, local pathogenicity, cardiac-specific expression, and population allele frequency. Performance was validated using variants for which the ClinVar pathogenicity assignment changed. Functional validation was assessed using prior studies in >900 identified VUS. The model utility was demonstrated using the Catheterization Genetics cohort. We identified a top-ranked model that accurately prioritized variants for which ClinVar clinical significance had changed (n=663; precision-recall area under the curve, 0.97) and performed well compared with conventional in silico methods. This model (CVD pathogenicity predictor) also had high accuracy in prioritizing VUS with functional effects in vivo (precision-recall area under the curve, 0.58). In Catheterization Genetics, there was a greater burden of higher CVD pathogenicity predictor scored VUS in individuals with dilated cardiomyopathy compared with controls (P=8.2×10-15). Of individuals in Catheterization Genetics who harbored highly ranked CVD pathogenicity predictor VUS meeting clinical pathogenicity criteria, 27.6% had clinical evidence of disease. Variant prioritization using this model increased genetic diagnosis in Catheterization Genetics participants with a known clinical diagnosis of hypertrophic cardiomyopathy (7.8%-27.2%). We present a cardiac-specific model for prioritizing variants underlying CVD syndromes with high performance in discriminating the pathogenicity of VUS in CVD genes. Variant review and phenotyping of individuals carrying VUS of pathogenic interest support the clinical utility of this model. This model could also have utility in filtering variants as part of large-scale genomic sequencing studies.

Novel ryanodine receptor 1 (RYR1) missense gene variants in two pet dogs with fatal malignant hyperthermia identified by next-generation sequencing

ObjectiveEvaluate a precision medicine approach to confirm a tentative diagnosis of fatal malignant hyperthermia (MH) in isoflurane-anesthetized pet dogs by identifying novel risk variants in known MH susceptibility genes. Study designRetrospective case series. AnimalsA male Pit Bull mix aged 7 years (case #1), a male Golden Retriever aged 12 months (case #2) and the dam and sire of case #2. MethodsAvailable case histories and medical records were reviewed. Missense variants in MH susceptibility genes RYR-1, CACNA1S and STAC3 (case #2 only) were identified by next-generation sequencing of DNA from each case and the parents of case #2 with confirmation by Sanger sequencing. The pathogenicity of variants was evaluated by multiple in silico approaches. ResultsBoth cases demonstrated clinical signs during isoflurane anesthesia consistent with volatile anesthetic-induced MH, including tachypnea, tachycardia, severe hyperthermia and muscle rigidity. Despite whole body cooling and other treatments, both dogs died after cardiac arrest within 15 minutes of detecting hyperthermia. Gene sequencing identified novel missense RYR-1 variants in case #1 (p.Gly2375Arg) and case #2 (p.Pro152Leu). Both variants were likely pathogenic based on multiple criteria, including gene location, amino acid alteration and population allele frequency. The case #1 variant was identical to a known human diagnostic MH variant (p.Gly2375Arg). Neither parent of case #2 had the case #2 variant, indicating this variant was not inherited, but arose de novo in a germ cell of either parent or early in embryogenesis. Whole genome sequence analysis confirmed parentage. Two missense variants were identified in CACNA1S. Both variants were considered nonpathogenic. No variants were identified in STAC3. Conclusions and clinical relevanceLike humans, MH susceptibility in dogs is associated with different rare variants located in pathogenic hotspots in the RYR-1 gene. Next-generation sequencing is a useful tool to assist in the definitive diagnosis of MH in dogs.

Abstract C051: Impact of population pharmacogenomics on cisplatin-induced neurotoxicities

Abstract Background: Studies have shown that taxane-treated breast cancer patients with African (AFR) ancestry experience worse peripheral sensory neuropathy (PSN), while African American vincristine-treated leukemia patients have less PSN than Europeans (EUR). We hypothesized that ancestral disparities may exist for cisplatin-induced neurotoxicities and may relate to differences in allele frequency and resultant gene expression of SNPs associated with these toxicities. Methods: In our Platinum Study of 1680 genotyped testicular cancer survivors (TCS), multidimensional scaling scores were anchored by the 1000 Genomes population to classify geographic ancestry. PSN (EORTC-CIPN20) and other toxicities plus clinical and lifestyle variables were examined for associations between geographic ancestry and phenotypes using logistic regression and Wilcoxon rank sum test. Genotyped SNPs with Fst > 0.25 in 1000 Genomes were identified and evaluated with GTEx data to find expression or splicing quantitative trait loci in nerve/brain tissue or for cisplatin-associated candidate genes, across all tissues. LDmatrix was used to find linkage disequilibrium. If a block of SNPs had R2 > 0.75, one independent SNP was kept for association analysis. Logistic regression with age at questionnaire completion and 10 genetic principal components as covariates was used to calculate the association between genotype and toxicity. Results: In an analysis of patients who received 400-450 mg/m2 of cisplatin including EUR (n=681), Asian (ASN) axis (n=44) and AFR (n=13), the odds ratio (OR) for any neuropathy vs. none in the AFR vs. EUR was 7.8 (P=0.049) and in the AFR vs. ASN axis (including East Asian 1000 Genomes populations) was 10.0 (P=0.034). TCS with AFR ancestry had significantly more vertigo. There were 19,874 SNPs for analysis from the genome-wide approach and 118 SNPs from the candidate gene approach. While associations between genotype and toxicity did not reach Bonferroni threshold, some SNPs had p-values in the 10-5 range. For PSN, one SNP had increased frequency of a risk allele in the AFR population while the other had increased frequency of a protective allele, while for vertigo, four SNPs had increased frequency of risk alleles in the AFR population. Of interest was rs34904346, in which the TT vs. AA genotype had an OR of 1.9 (p=2x10-5) for any vs. no PSN, with the T allele having 90% frequency in AFR ancestry patients versus ∼60% in other populations. This SNP and three other independent SNPs associated with PSN incidence (p∼10-3) are eQTLs for RNF24 in nerve tissue, which interacts with membrane proteins that regulate intracellular calcium levels. Conclusions: We show preliminary evidence for the role of differing risk allele frequencies across populations in explaining disparities in cisplatin-induced PSN and vertigo, likely in combination with structural and environmental factors. Genotyping risk alleles could customize dosing, treatment, and post-treatment monitoring to benefit all cisplatin-treated patients. Citation Format: Swetha Nakshatri, Paul C. Dinh, Darren R. Feldman, Robert J. Hamilton, Chunkit Fung, David J. Vaughn, Christian Kollmannsberger, Robert Huddart, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis, Eileen Dolan. Impact of population pharmacogenomics on cisplatin-induced neurotoxicities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C051.

Increased incidences of cervical ribs in deer indicate extinction risk

Mammals as a rule have seven cervical vertebrae, a number which remains remarkably conserved. Occasional deviations of this number are usually due to the presence of cervical ribs on the seventh vertebra, indicating a homeotic transformation from a cervical rib-less vertebra into a thoracic rib-bearing vertebra. These transformations are often associated with major congenital abnormalities or pediatric cancers (pleiotropic effects) that are, at least in humans, strongly selected against. Based on data from Late Pleistocene mammoths (Mammuthus primigenius) and woolly rhinoceroses (Coelodonta antiquitatis) from the North Sea, we hypothesized that high incidences of cervical ribs in declining populations are due to inbreeding and/or adverse conditions impacting early pregnancies. In this study, we investigated the incidence of cervical ribs in an extinct Late Pleistocene megaherbivore, giant deer (Megaloceros giganteus) from Ireland and in the extant highly inbred Père David deer (Elaphurus davidianus) and in twenty other extant species. We show that the incidence of cervical ribs is exceptionally high in both the Irish giant deer and the Père David deer and much higher than in extant outbred deer. Our data support the hypothesis that inbreeding and genetic drift increase the frequencies of maladaptive alleles in populations at risk of extinction. The high incidence of cervical ribs indicates a vulnerable condition, which may have contributed to the extinction of megaherbivore species in the Late Pleistocene. We argue that cervical rib frequency may be a good proxy for extinction risk in inbred populations.

Expanding the Russian allele frequency reference via cross-laboratory data integration: insights from 7452 exome samples.

Population allele frequency is crucially important for accurate interpretation of known and novel variants in medical genetics. Recently, several large allele frequency databases, such as the Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency is often more informative than the global one. Many countries and regions, including Russia, remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct RUSeq, an open, large-scale reference set of genetic variants by analyzing 7452 exome samples collected in two major Russian cities-Moscow and St. Petersburg. An ∼10-fold increase in sample size compared to previous studies allowed us to characterize extensive genetic diversity within the admixed Russian population with contributions from several major ancestral groups. We highlight 51 known pathogenic variants that are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite being annotated as pathogenic in ClinVar and falling within genes associated with autosomal dominant disorders. The constructed database of genetic variant frequencies in Russia has been made available to the medical genetics community through a variant browser available at http://ruseq.ru.

AGT, CYP11B2 & ADRB2 gene polymorphism & essential hypertension (HT): A meta-analysis.

Background & objectives The results of the genetic association studies between the selected candidate genes and hypertension (HT) contradicted across different populations. Majority of the meta-analyses carried out did not consider population genetic ancestry as a confounding factor. Therefore, this meta-analysis attempted to consolidate and re-evaluate the findings of the association between the selected candidate variants (AGT-rs699, CYP11B2-rs1799998, ADRB2-rs1042713 and rs1042714) and HT, by categorizing the genotyping data based on known genetic ancestry, and/or major geographical populations. Methods Publications were retrieved from PubMed, Cochrane and World of Science. The included articles were further divided into different populations based on their known genetic and/or geographical ancestry. Results AGTrs699-G was significantly associated with HT among Indians for (i) allele [P=0.03, Odds ratio (OR): 1.37, 95% Confidence Interval (CI): 1.03-1.82], and (ii) dominant mode of inheritance (P=0.009, OR:1.45, 95% CI: 1.09-1.91). CYP11B2rs1799998-G was significantly associated with HT in Europeans for (i) allele (P=6.9 × 10-5, OR: 0.82, 95% CI: 0.74-0.9), (ii) recessive (P=6.38 × 10-5, OR: 0.7, 95% CI: 0.59-0.83) and (iii) dominant mode of inheritance (P=0.008, OR: 0.81, 95% CI: 0.7-0.94). ADRB2-rs1042713-G was significantly associated with HT in east Asians for (i) allele (P=0.01, OR: 1.26, 95% CI: 1.05-1.51), and (ii) recessive mode of inheritance (P=0.04, OR: 1.36, 95% CI: 1.01-1.83). Interpretation & conclusions Different genotype and allele frequencies in diverse populations result in different genetic associations with HT across populations. This meta-analysis finding provides an update and summary of the genetic association between the selected simple nucleotide polymorphism (SNPs) and HT across different populations and essential insights into selecting appropriate pharmacogenetic marker(s) for effective HT management in populations of different ancestries.

Geographical distribution of MTHFR C677T gene polymorphisms among the reproductive-age women in Chinese Han populations: based on migration

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is essential for the metabolism of folic acid and homocysteine. The MTHFR C677T polymorphism is associated with several disorders. Our study aims to explore the geographical distributions of the MTHFR C677T polymorphism of women in China and how migration affected the polymorphism in Suzhou.MethodsA total of 7188 women of reproductive age were recruited in Suzhou of the study. Subjects were classified according to their native places after data extraction. MTHFR C677T gene polymorphisms were detected by quantitative PCR with genomic DNA isolated from blood samples.ResultsThe frequencies of the 677T allele and 677TT genotype were higher in northern China than that in southern China and decreased in geographical gradients from north to south. The frequencies were considerably higher in the migrant population than that in the indigenous population of Suzhou. The migrant population have gradually changed the prevalence in Suzhou.ConclusionsOur study suggested that the prevalence of MTHFR C677T polymorphisms among women varied across different geographical regions in Chinese Han populations. The 677T allele frequencies of the northern populations were significantly higher than those of the southern populations. The migrant population gradually changed the prevalence of the MTHFR C677T polymorphism in Suzhou.

Molecular genetic analysis of candidate genes for glutaric aciduria type II in a cohort of patients from Queensland, Australia

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.

Variant ranking pipeline for complex familial disorders

Identifying genetic susceptibility factors for complex disorders remains a challenging task. To analyze collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible, we have developed a weights-based pipeline to prioritize variants and genes. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 and 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. N/A. The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Further delineation of short-chain enoyl-CoA hydratase deficiency in the Pacific population

Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic pathogenic ECHS1 variants was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. It is potentially treatable with a valine-restricted, high-energy diet and emergency regimen. Recently, Simon et al. described four Samoan children harbouring a hypomorphic allele (c.489G>A, p.Pro163=) associated with reduced levels of normally-spliced mRNA. This synonymous variant, missed on standard genomic testing, is prevalent in the Samoan population (allele frequency 0.17). Patients with LS and one ECHS1 variant were identified in NZ and Australian genomic and clinical databases. ECHS1 sequence data were interrogated for the c.489G>A variant and clinical data were reviewed. Thirteen patients from 10 families were identified; all had Pacific ancestry including Samoan, Māori, Cook Island Māori, and Tokelauan. All developed bilateral globus pallidi lesions, excluding one pre-symptomatic infant. Symptom onset was in early childhood, and was triggered by illness or starvation in 9/13. Four of 13 had exercise-induced dyskinesia, 9/13 optic atrophy and 6/13 nystagmus. Urine S-(2-carboxypropyl)cysteine-carnitine and other SCEH-related metabolites were normal or mildly increased. Functional studies demonstrated skipping of exon four and markedly reduced ECHS1 protein. These data provide further support for the pathogenicity of this ECHS1 variant which is also prevalent in Māori, Cook Island Māori, and Tongan populations (allele frequency 0.14-0.24). It highlights the need to search for a second variant in apparent heterozygotes with an appropriate phenotype, and has implications for genetic counselling in family members who are heterozygous for the more severe ECHS1 alleles. SYNOPSIS: Short-chain enoyl-CoA hydratase deficiency is a frequent cause of Leigh-like disease in Māori and wider-Pacific populations, due to the high carrier frequency of a hypomorphic ECHS1 variant c.489G>A, p.[Pro163=, Phe139Valfs*65] that may be overlooked by standard genomic testing.

Assisting the analysis of insertions and deletions using regional allele frequencies.

Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides "regional AF" (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (n=125,748 samples), an internal dataset (IGM; n=39,367), and the UK BioBank (UKBB; n=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10-4 and rAF>10-4) as "rAF-hi" indels. Notably, a high percentage of rare indels were "rAF-hi", with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels' parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.

Individual and population-level variability in HLA-DR associated immunogenicity risk of biologics used for the treatment of rheumatoid arthritis.

While conventional in silico immunogenicity risk assessments focus on measuring immunogenicity based on the potential of therapeutic proteins to be processed and presented by a global population-wide set of human leukocyte antigen (HLA) alleles to T cells, future refinements might adjust for HLA allele frequencies in different geographic regions or populations, as well for as individuals in those populations. Adjustment by HLA allele distribution may reveal risk patterns that are specific to population groups or individuals, which current methods that rely on global-population HLA prevalence may obscure. This analysis uses HLA frequency-weighted binding predictions to define immunogenicity risk for global and sub-global populations. A comparison of assessments tuned for North American/European versus Japanese/Asian populations suggests that the potential for anti-therapeutic responses (anti-therapeutic antibodies or ATA) for several commonly prescribed Rheumatoid Arthritis (RA) therapeutic biologics may differ, significantly, between the Caucasian and Japanese populations. This appears to align with reports of differing product-related immunogenicity that is observed in different populations. Further definition of population-level (regional) and individual patient-specific immunogenic risk profiles may enable prescription of the RA therapeutic with the highest probability of success to each patient, depending on their population of origin and/or their individual HLA background. Furthermore, HLA-specific immunogenicity outcomes data are limited, thus there is a need to expand HLA-association studies that examine the relationship between HLA haplotype and ATA in the clinic.

PNPLA3 fatty liver allele was fixed in Neanderthals and segregates neutrally in humans

ObjectiveFat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and...

Multiomic analysis of uterine leiomyomas in self-described Black and White women: molecular insights into health disparities

Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients. To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women. We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses. We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38. Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations.

Locally adaptive inversions in structured populations.

Inversions have been proposed to facilitate local adaptation, by linking together locally coadapted alleles at different loci. Prior work addressing this question theoretically has considered the spread of inversions in "continent-island" scenarios in which there is a unidirectional flow of maladapted migrants into the island population. In this setting, inversions capturing locally adaptive haplotypes are most likely to invade when selection is weak, because stronger local selection (i) more effectively purges maladaptive alleles and (ii) generates linkage disequilibrium between adaptive alleles, thus lessening the advantage of inversions. We show this finding only holds under limited conditions by studying the establishment of inversions in a more general two-deme model, which explicitly considers the dynamics of allele frequencies in both populations linked by bidirectional migration. In this model, the level of symmetry between demes can be varied from complete asymmetry (continent-island) to complete symmetry. For symmetric selection and migration, strong selection increases the allele frequency divergence between demes thereby increasing the frequency of maladaptive alleles in migrants, favoring inversions-the opposite of the pattern seen in the asymmetric continent-island scenario. We also account for the likelihood that a new inversion captures an adaptive haplotype in the first instance. When considering the combined process of capture and invasion in "continent island" and symmetric scenarios, relatively strong selection increases inversion establishment probability. Migration must also be low enough that the inversion is likely to capture an adaptive allele combination, but not so low as to eliminate the inversion's advantage. Overall, our analysis suggests that inversions are likely to harbor larger effect alleles that experience relatively strong selection.

Cardiac arrhythmia and epilepsy genetic variants in sudden unexpected death in epilepsy.

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading epilepsy-related cause of death, affecting approximately 1 per 1,000 individuals with epilepsy per year. Genetic variants that affect autonomic function, such as genes associated with cardiac arrhythmias, may predispose people with epilepsy to greater risk of both sudden cardiac death and SUDEP. Advances in next generation sequencing allow for the exploration of gene variants as potential biomarkers. Genetic testing for the presence of cardiac arrhythmia and epilepsy gene variants was performed via genetic panels in 39 cases of SUDEP identified via autopsy by the Ontario Forensic Pathology Service. Variants were summarized by in-silico evidence for pathogenicity from 4 algorithms (SIFT, PolyPhen-2, PROVEAN, Mutation Taster) and allele frequencies in the general population (GnomAD). A maximum credible population allele frequency of 0.00004 was calculated based on epilepsy prevalence and SUDEP incidence to assess whether a variant was compatible with a pathogenic interpretation. Median age at the time of death was 33.3 years (range: 2, 60). Fifty-nine percent (n=23) were male. Gene panels detected 62 unique variants in 45 genes: 19 on the arrhythmia panel and 26 on the epilepsy panel. At least one variant was identified in 28 (72%) of decedents. Missense mutations comprised 57 (92%) of the observed variants. At least three in silico models predicted 12 (46%) cardiac arrhythmia panel missense variants and 20 (65%) epilepsy panel missense variants were pathogenic. Population allele frequencies were <0.00004 for 11 (42%) of the cardiac variants and 10 (32%) of the epilepsy variants. Together, these metrics identified 13 SUDEP variants of interest. Nearly three-quarters of decedents in this SUDEP cohort carried variants in comprehensive epilepsy or cardiac arrhythmia gene panels, with more than a third having variants in both panels. The proportion of decedents with cardiac variants aligns with recent studies of the disproportionate cardiac burden the epilepsy community faces compared to the general population and suggests a possible cardiac contribution to epilepsy mortality. These results identified 13 priority targets for future functional studies of these genes potential role in sudden death and demonstrates the necessity for further exploration of potential genetic contributions to SUDEP.