Common Haplotype Research Articles

Polymorphisms of the Vitamin D Binding Protein (VDBP) and Free Vitamin D in Patients with Cystic Fibrosis

Objectives/Background: Vitamin D-binding protein (VDBP) and free vitamin D are new markers that are being studied as a possible markers of vitamin D status. The main aim of our study was to analyze the VDBP genotype and quantify the levels of free vitamin D in a sample of cystic fibrosis (CF) patients. Methods: We conducted a multicenter, cross-sectional, and prospective study including patients with CF and exocrine pancreatic insufficiency who were clinically stable. We investigated vitamin D levels (total and free) and the different VDBP haplotypes. Free vitamin D levels were measured using an electro-chemiluminescence assay. Results: A sample of 48 patients was obtained (52% male; median age 13.8 years). The most common allele of VDBP was Gc1s (72%) > Gc2 (52%) > Gc1f (27%). The median calcidiol was 21.2 ng/mL (IR 15.3–26.9), and 81% had levels in the insufficiency range: 23 patients (48%) below 20 ng/mL, and 16 (33%) between 20 and 30 ng/mL. The median free vitamin D level was 4.2 pg/mL (IR 3.9–5.6). A positive correlation was observed between calcidiol and free vitamin D levels (r = 0.871; p < 0.0001). After adjustment for season, vitamin D supplementation, sex, and CF-related diabetes, patients with Gc1f polymorphism had a lower risk of vitamin D deficiency, OR 0.22 (95% CI 0.05–0.99), and p = 0.027. A negative linear trend was observed between the polymorphisms grouped into three categories (Gc1/Gc1, Gc1/Gc2, and Gc2/Gc2, in that order) and vitamin D and free vitamin D levels (p = 0.025 and p = 0.033, respectively). Conclusion: In CF, as in the general population, the most common VDBP haplotype in the Caucasian race is Gc1s. VDBP polymorphisms influence serum vitamin D and free vitamin D levels in CF patients. There is a good correlation between free vitamin D and calcidiol levels, suggesting that measuring the latter in CF does not seem to provide any additional benefit.

Reconstruction of the human amylase locus reveals ancient duplications seeding modern-day variation.

Previous studies suggested that the copy number of the human salivary amylase gene, AMY1, correlates with starch-rich diets. However, evolutionary analyses are hampered by the absence of accurate, sequence-resolved haplotype variation maps. We identified 30 structurally distinct haplotypes at nucleotide resolution among 98 present-day humans, revealing that the coding sequences of AMY1 copies are evolving under negative selection. Genomic analyses of these haplotypes in archaic hominins and ancient human genomes suggest that a common three-copy haplotype, dating as far back as 800 KYA, has seeded rapidly evolving rearrangements through recurrent non-allelic homologous recombination. Additionally, haplotypes with more than three AMY1 copies have significantly increased in frequency among European farmers over the past 4,000 years, potentially as an adaptive response to increased starch digestion.

Impact of TAS2R38 polymorphisms on nasal nitric oxide and Pseudomonas infections in primary ciliary dyskinesia: relation to genotype

ObjectivePrimary ciliary dyskinesia (PCD) severity has been related to genotype and levels of nasal nitric oxide (nNO). The most common TAS2R38 haplotypes (PAV/PAV, PAV/AVI, AVI/AVI) encoding the bitter taste receptor...

Genetic relationships of populations of the Black Kite Milvus migrans (Accipitriformes: Accipitridae) in the east of its range in Asia and Australia

While the Black Kite Milvus migrans is one of the most widespread birds of prey, occurring over Eurasia, Africa and Australia, it remains poorly understood outside of Europe, with southeast Asian populations particularly mysterious as their taxonomy is based on outdated morphological data. The subspecies M. m. formosanus, described in 1920, is thought to inhabit Taiwan and Hainan; however, populations in these areas have experienced dramatic changes over the past fifty years. Furthermore, M. m. formosanus is the only officially recognised subspecies for which almost no genetic data is yet available. Based on two mitochondrial genes, we compared Taiwanese Black Kites with northeast Asian and Japanese M. m. lineatus, Indian M. m. govinda and Australian M. m. affinis to reconstruct details of their population history. While Indian and Australian Black Kites are descendants of the same population, they do not share common haplotypes, probably having diverged by the end of the last glaciation. The Japanese population is distinctive in showing genetic uniformity, and it may be isolated from the mainland population. Nesting Taiwanese kites carry two previously known M. m. lineatus haplogroups and a new haplogroup possibly inherited from M. m. formosanus previously occurring in the area. A recent decline in the local population, along with expansion of M. m. lineatus, most likely led to Taiwan now being inhabited by descendants of both subspecies, which form two genetically isolated populations in southern and northern Taiwan.

Mucopolysaccharidosis type I: founder effect of the p.P533R mutation in North Africa

BackgroundMucopolysaccharidosis type I is a lysosomal storage disease resulting from a deficiency in alpha-L-iduronidase (IDUA), which causes the accumulation of partially degraded dermatan sulfate and heparan sulfate. This retrospective study, spanning eight years, analyzed data from 45 MPSI patients. The report aimed to explore the potential origin of the p.P533R mutation in the Maghrebin population by constructing a single-nucleotide polymorphism haplotype around the IDUA gene, in order to propose a molecular proof of a founder effect of the MPSI/p.P533R allele.Patients and methodsAll of the studied patients were from Libya (2), Mauritania (1) Morocco (21) and Tunisia (21) with first cousins being the most frequent union. The diagnosis of MPSI patients often involves the combination of urinary screening, leukocyte IDUA activity determination, and DNA molecular analysis. In our study, to identify the common p.P533R mutation, we performed both DNA sequencing and tetra-primer ARMS PCR assay. Additionally, Haploview was used to determine the specific haplotype that cosegregates with the p.P533R mutation. Controls were genotyped to ensure that all the SNPs were in Hardy–Weinberg equilibrium.ResultsIn the present report we confirmed the very strong impact of consanguinity on the incidence of MPSI disease. Furthermore, studied families of mixed ancestry shared common and specific haplotype, which was observed in studied populations, suggesting the presence of a founder effect in the North Africa.ConclusionThe p.P533R missense mutation was identified in each patient originated from Libya, Mauritania, Morocco and Tunisia. Furthermore, these MPSI patients exhibited the same IDUA haplotype. The occurrence of a shared AAGGGTG haplotype, among North African populations may be attributed to substantial historical gene exchange between these groups, likely stemming from migration, inter-ethnic marriage, or other forms of interaction throughout history.

Revealing the Genetic Differentiation of Rattus norvegicus (Berkenhout 1769) Populations by Analyzing Two Mitochondrial Markers

Rattus norvegicus (Brown rat) has a great importance for public health and economy because it lives in close association with human populations. However, molecular systematic studies on global populations of R. norvegicus are very few. In this study, sequences obtained from Europe, Asia, Africa, and America regions were analyzed using mitochondrial Cytochrome-b and Cytochrome oxidase-I gene regions and genetic differentiation levels between these populations were revealed. Accordingly, samples belonging to the studied populations did not split in Bayesian Inference trees and Median-joining networks; these samples also formed common haplotypes, and mean genetic distance and fixation index values were generally low. The results of the study showed that gene flow between these populations may be continuing due to the transportation activity by humans.

CbCyp51-Mediated Demethylation Inhibitor Resistance Is Modulated by Codon Bias.

Cercospora leaf spot, caused by the fungus Cercospora beticola, is the most destructive foliar disease of sugarbeet worldwide. Resistance to the sterol demethylation inhibitor (DMI) fungicide tetraconazole has been previously correlated with synonymous and nonsynonymous mutations in CbCyp51. Here, we extend these analyses to the DMI fungicides prothioconazole, difenoconazole, and mefentrifluconazole in addition to tetraconazole to confirm whether the synonymous and nonsynonymous mutations at amino acid positions 144 and 170 are associated with resistance to these fungicides. Nearly half of the 593 isolates of C. beticola collected in the Red River Valley of North Dakota and Minnesota in 2021 were resistant to all four DMIs. Another 20% were resistant to tetraconazole and prothioconazole but sensitive to difenoconazole and mefentrifluconazole. A total of 13% of isolates were sensitive to all DMIs tested. We found five CbCyp51 haplotypes and associated them with phenotypes to the four DMIs. The most predominant haplotype (E170_A/L144F_C) correlated with resistance to all four DMIs with up to 97.6% accuracy. The second most common haplotype (E170_A/L144) consisted of isolates associated with resistance phenotypes to tetraconazole and prothioconazole while also exhibiting sensitive phenotypes to difenoconazole and mefentrifluconazole with up to 98.4% accuracy. Quantitative PCR did not identify differences in CbCyp51 expression between haplotypes. This study offers an understanding of the importance of codon usage in fungicide resistance and provides crop management acuity for fungicide application decision-making.

Genetic variation of FUT3 gene in the Han population from Northern China.

The FUT3 gene encodes α(1,3/1,4)-fucosyltransferase, which is a crucial enzyme in the synthesis of Lewis antigens. FUT3 gene variants show race-specific differences. In this study, we conducted a systematic sequence analysis of the FUT3 coding sequence. The objective was to explore genetic variations of the FUT3 gene within the Han population of Northern China. A cohort of 313 blood donors was recruited for the study. The coding sequence of the FUT3 gene was amplified using polymerase chain reaction, followed by sequencing and haplotype construction. Twelve single nucleotide variations (SNVs) were identified within the coding sequence of the FUT3 gene. Notably, the c.59 T > G site exhibited the highest mutation frequency of 43.13%, followed by the c.508G > A and c.1067 T > A sites with mutation frequencies of 27.48% and 16.93%, respectively. Le was the most common haplotype, accounting for 67.57% of the cases, and Le/Le was the most common diplotype, accounting for 46.33% of the cases. The study also highlighted a significant difference in mutation frequencies of FUT3 gene between the Han Chinese of Northern China and the Dai of Xishuangbanna, China, but not the Han Chinese in Beijing in the North and the Southern Han Chinese, emphasising that Han Chinese in Northern China are genetically most distant from Europeans and closest to East Asians. Our study characterises FUT3 gene variations in Han Chinese from Northern China, and provides basic genetic data for genetics, forensic medicine, and genotyping of Lewis blood groups.

Long‐Term Maintenance of Complex Chromosomal Inversion Polymorphism in Drosophila mediopunctata

ABSTRACTNatural selection is known to favor specific gene combinations, thereby shaping the evolution of recombination rates, often through epistatic interactions. However, the dynamics of these interacting factors within natural populations remain poorly understood. In this study, we investigate the long‐term maintenance of a complex polymorphism involving linked, nonoverlapping chromosomal inversions in a natural population of Drosophila mediopunctata. Remarkably, even after 30 years—equivalent to roughly 340 generations—two major features have remained unexpectedly stable: the linkage disequilibrium (LD) between inversions, which deviates significantly from the theoretical prediction of decay, and a consistent seasonal cycle pattern of heterozygous excess and homozygous deficiencies. We explored the roles of recombination suppression, epistatic selection, and overdominance in maintaining this stability, examining their alignment with previously described patterns. Our findings reveal that moderate selection coefficients, such as s = 0.0407, are sufficient to maintain the observed LD for the most common haplotypes, albeit leading to an unstable equilibrium. Simulations further reveal that the introduction of overdominance stabilizes the system, enabling the long‐term persistence of this complex inversion polymorphism across various frequency scenarios. The stability of this system appears to hinge on a delicate balance between LD, recombination rates, and selective pressures, with overdominance playing a critical role. Our findings highlight the significance of epistatic interactions and selective pressures in shaping evolutionary pathways in natural populations and offer a compelling example of natural selection acting on a complex inversion polymorphism, providing valuable insights into the evolutionary dynamics governing inversion systems.

The LRRK2 p.L1795F variant causes Parkinson's disease in the European population.

Pathogenic variants in the LRRK2 gene represent the most common cause of autosomal dominant Parkinson's disease (PD) worldwide. We identified the LRRK2 p.L1795F variant in 14 White/European ancestry PD patients, including two families with multiple affected carriers and seven additional affected individuals with familial PD using genotyping and sequencing data from more than 50,000 individuals through GP2, AMP-PD, PDGENEration, and CENTOGENE. All variant carriers were of White/European ancestry, and those with available genotyping data shared a common haplotype. The clinical presentation of p.L1795F carriers resembles that of other LRRK2 pathogenic variant carriers. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, our findings provide conclusive evidence that the LRRK2 p.L1795F variant is pathogenic. It represents a rare cause of PD in the European population but needs to be included in genetic testing efforts and considered for ongoing gene-specific clinical trials.

Calculated Panel Reactive Antibody for an Organ-Sharing Zone: Concept and Execution Based on Data from North Kerala

Background Calculated-PRA (CPRA) is derived by virtually matching a recipient’s antibody profile against HLA antigens of a representative donor pool of a geographical region. Materials and Methods An android application–based CPRA calculator was created from HLA typing data (A/B/DR loci) of 712 consecutive living donors spanning over last 10 years from an organ-sharing region in Kerala. Only an open-source software was used. Results Our HLA data, compared with the National Marrow Donor Program (NMDP) 2011 database, show that the most common haplotype frequencies show comparable positions in order of prevalence. Available online PRA calculators like OPTN and Canadian CPRA show significant differences in PRA estimation when used in our population. This calculator provides a more accurate and realistic estimate of sensitization against the representative donor pool. Conclusion This CPRA tool can be customized for any allocation region using portable open-source software. The donor pool can be updated continually by populating data from multiple regional centers.

C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan

A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.

Mapping the immunopeptidome of seven SARS-CoV-2 antigens across common HLA haplotypes

Most COVID-19 vaccines elicit immunity against the SARS-CoV-2 Spike protein. However, Spike protein mutations in emerging strains and immune evasion by the SARS-CoV-2 virus demonstrates the need to develop more broadly targeting vaccines. To facilitate this, we use mass spectrometry to identify immunopeptides derived from seven relatively conserved structural and non-structural SARS-CoV-2 proteins (N, E, Nsp1/4/5/8/9). We use two different B-lymphoblastoid cell lines to map Human Leukocyte Antigen (HLA) class I and class II immunopeptidomes covering some of the prevalent HLA types across the global human population. We employ DNA plasmid transfection and direct antigen delivery approaches to sample different antigens and find 248 unique HLA class I and HLA class II bound peptides with 71 derived from N, 12 from E, 28 from Nsp1, 19 from Nsp4, 73 from Nsp8 and 45 peptides derived from Nsp9. Over half of the viral peptides are unpublished. T cell reactivity tested against 56 of the detected peptides shows CD8+ and CD4+ T cell responses against several peptides from the N, E, and Nsp9 proteins. Results from this study will aid the development of next-generation COVID vaccines targeting epitopes from across a number of SARS-CoV-2 proteins.

Genetic diversity of Dotilla myctiroides (Crustacea: Brachyura: Dotillidae) based on mitochondrial cox1 gene marker in Peninsular Malaysia

ABSTRACT The present study examined the genetic diversity of two populations of Dotilla myctiroides (Milne-Edwards) from Peninsular Malaysia. Based on 640-bp COX1 (cytochrome c oxidase subunit 1) gene sequences, the D. myctiroides specimens from Peninsular Malaysia, Singapore and India formed a lineage which was distinctly separated from Dotilla wichmanni and D. fenestrata. Sixteen COX1 haplotypes were found in Peninsular Malaysia samples, with 11 haplotypes in the Morib sample, eight in the Tanjung Tuan sample, and three common haplotypes in these samples. The Singapore specimen had the commonest haplotype of Peninsular Malaysia, while the Indian specimen had a distinct haplotype. The proportions of the two most common COX1 haplotypes were not significantly different between the Morib and Tanjung Tuan samples. The difference in the mean haplotype diversity between these samples was statistically significant. However, the nucleotide diversity of the two samples was not significantly different and there was no genetic subdivision/differentiation between the two populations. The high number of closely related haplotypes indicates the possibility of a recent population expansion. The data provide valuable information for future studies on the genetic diversity, population structure and phylogeography of Dotilla species.

Insights into maydis leaf blight resistance in maize: a comprehensive genome-wide association study in sub-tropics of India

BackgroundIn the face of contemporary climatic vulnerabilities and escalating global temperatures, the prevalence of maydis leaf blight (MLB) poses a potential threat to maize production. This study endeavours to discern marker-trait associations and elucidate the candidate genes that underlie resistance to MLB in maize by employing a diverse panel comprising 336 lines. The panel was screening for MLB across four environments, employing standard artificial inoculation techniques. Genome-wide association studies (GWAS) and haplotype analysis were conducted utilizing a total of 128,490 SNPs obtained from genotyping-by-sequencing (GBS).ResultsGWAS identified 26 highly significant SNPs associated with MLB resistance, among the markers examined. Seven of these SNPs, reported in novel chromosomal bins (9.06, 5.01, 9.01, 7.04, 4.06, 1.04, and 6.05) were associated with genes: bzip23, NAGS1, CDPK7, aspartic proteinase NEP-2, VQ4, and Wun1, which were characterized for their roles in diminishing fungal activity, fortifying defence mechanisms against necrotrophic pathogens, modulating phyto-hormone signalling, and orchestrating oxidative burst responses. Gene mining approach identified 22 potential candidate genes associated with SNPs due to their functional relevance to resistance against necrotrophic pathogens. Notably, bin 8.06, which hosts five SNPs, showed a connection to defense-regulating genes against MLB, indicating the potential formation of a functional gene cluster that triggers a cascade of reactions against MLB. In silico studies revealed gene expression levels exceeding ten fragments per kilobase million (FPKM) for most genes and demonstrated coexpression among all candidate genes in the coexpression network. Haplotype regression analysis revealed the association of 13 common significant haplotypes at Bonferroni ≤ 0.05. The phenotypic variance explained by these significant haplotypes ranged from low to moderate, suggesting a breeding strategy that combines multiple resistance alleles to enhance resistance to MLB. Additionally, one particular haplotype block (Hap_8.3) was found to consist of two SNPs (S8_152715134, S8_152460815) identified in GWAS with 9.45% variation explained (PVE).ConclusionThe identified SNPs/ haplotypes associated with the trait of interest contribute to the enrichment of allelic diversity and hold direct applicability in Genomics Assisted Breeding for enhancing MLB resistance in maize.

Renin-Angiotensin System Genes Polymorphisms in Patients With COVID-19 and Its Relation to Severe Cases of SARS-CoV-2 Infection.

Different variants of single nucleotide polymorphisms (SNPs) of angiotensinogen (AGT), angiotensin-converting enzyme type 1 (ACE1), and angiotensin II receptors type 1 (AGTR1) and 2 (AGTR2) genes determine different susceptibility to cardiovascular disease (CVD) and hypertension, which can be considered as risk factors for fatal outcomes among coronavirus disease 2019 (COVID-19) patients. The objective of our study was to assess the relation between the frequency of SNPs of the renin-angiotensin system (RAS) components, and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The cross-sectional study included 100 patients with a laboratory-confirmed diagnosis of COVID-19 admitted to the hospital. Criteria for severe COVID-19 included respiratory rate (RR) > 30/min, blood oxygen saturation (SpO2) ≤ 93%, signs of unstable hemodynamics with systolic blood pressure (SBP) < 90 and/or diastolic blood pressure (DBP) < 60 mm Hg. All patients were identified with alleles and genotypes of the polymorphic markers rs4762 of the AGT gene, rs1799752 of the ACE1 gene, rs5186 of the AGTR1 gene and rs1403543 of the AGTR2 gene using the polymerase chain reaction method in human DNA preparations on real-time CFX96C1000 Touch, Bio-Rad equipment (Syntol, Russia). Statistical analysis was performed in R v.4.2. Patients were divided into groups with severe (n = 44) and moderate COVID-19 (n = 56). For ACE1 rs1799752, a significant deviation from the population distribution was detected in both studied subgroups. A higher frequency of the C allele SNP rs5186 AGTR1 gene was detected in the group with severe disease. More frequent A/A genotype of SNP rs1403543 AGTR2 was detected among females with severe COVID-19. Haplotype analysis revealed more common DCG haplotype among patients with severe COVID-19. The odds ratio for severe COVID-19 in the presence of the DCG haplotype was 3.996 (95% confidential interval: 1.080 -14.791, P < 0.05). Our data suggest that the SNP genes of the RAS components, may allow to identify groups of patients predisposed to a more severe course of COVID-19.

Disparities in Genetic Diversity Drive the Population Displacement of Two Invasive Cryptic Species of the Bemisia tabaci Complex in China.

Within the whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) complex, two cryptic species, namely Middle East-Asia Minor 1 (MEAM1) and Mediterranean (MED), are important invasive pests affecting global agriculture and horticulture. They were introduced into China sequentially in the mid-1990s and around 2003, respectively. Subsequently, the latter invader MED has outcompeted the earlier invader MEAM1, becoming the dominant population in the field. Although extensive studies have explored the underlying mechanisms driving this shift, the contribution of population genetics remains notably underexplored. In this study, we analyzed the genetic diversity and structure of 22 MED and 8 MEAM1 populations from various regions of China using mitochondrial DNA sequencing and microsatellite genotyping. Our results indicate low and moderate levels of genetic differentiation among geographically separate populations of MED and MEAM1, respectively. Median-joining network analysis of mtCOI gene haplotypes revealed no clear geographic structuring for either, with common haplotypes observed across provinces, although MED had more haplotypes. Comparative analyses revealed that MED presented greater genetic diversity than MEAM1 on the basis of two markers. Furthermore, analysis of molecular variance supported these findings, suggesting that while some genetic variation exists between populations, a significant amount is also present within populations. These findings reveal the population genetics of the two invasive cryptic species of the B. tabaci complex in China and suggest that the disparities in genetic diversity drive the displacement of their populations in the field. This work also provides valuable information on the genetic factors influencing the population dynamics and dominance of these invasive whitefly species.

New COI-COII mtDNA Region Haplotypes in the Endemic Honey Bees Apis mellifera intermissa and Apis mellifera sahariensis (Hymenoptera: Apidae) in Algeria.

The practice of beekeeping in Algeria is of great cultural, social, and economic importance. However, the importation of non-local subspecies reported by beekeepers has disrupted the natural geographical distribution area and the genetic diversity of the native honey bees. To assess the genetic diversity of A. m. intermissa and A. m. sahariensis, and their relationships with African and European subspecies, the COI-COII intergenic region was analyzed in 335 individuals, 68 sampled in Algeria, 71 in Europe, Madagascar, and the South West Indian Ocean archipelagos, and 196 sequences recovered from GenBank. The results show the presence of the A lineage exclusively in Algerian samples with the identification of 24 haplotypes of which 16 are described for the first time. These haplotypes were found to be shared by both subspecies, with A74 being the most common haplotype in the population studied. The sequence comparison indicates the existence of three polymorphisms of the COI-COII marker: P0Q, P0QQ, and P0QQQ. One new haplotype was identified in the M lineage in samples from France. No evidence of genetic introgression within the Algerian honey bee population was detected. These data enhance our knowledge of the genetic diversity and emphasize the importance of protecting these local subspecies.

Common and rare genetic variants predisposing females to unexplained recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is a major reproductive health issue with multifactorial causes, affecting 2.6% of all pregnancies worldwide. Nearly half of the RPL cases lack clinically identifiable causes (e.g., antiphospholipid syndrome, uterine anomalies, and parental chromosomal abnormalities), referred to as unexplained RPL (uRPL). Here, we perform a genome-wide association study focusing on uRPL in 1,728 cases and 24,315 female controls of Japanese ancestry. We detect significant associations in the major histocompatibility complex (MHC) region at 6p21 (lead variant=rs9263738; P = 1.4 × 10−10; odds ratio [OR] = 1.51 [95% CI: 1.33–1.72]; risk allele frequency = 0.871). The MHC associations are fine-mapped to the classical HLA alleles, HLA-C*12:02, HLA-B*52:01, and HLA-DRB1*15:02 (P = 1.1 × 10−10, 1.5 × 10−10, and 1.2 × 10−9, respectively), which constitute a population-specific common long-range haplotype with a protective effect (P = 2.8 × 10−10; OR = 0.65 [95% CI: 0.57–0.75]; haplotype frequency=0.108). Genome-wide copy-number variation (CNV) calling demonstrates rare predicted loss-of-function (pLoF) variants of the cadherin-11 gene (CDH11) conferring the risk of uRPL (P = 1.3 × 10−4; OR = 3.29 [95% CI: 1.78–5.76]). Our study highlights the importance of reproductive immunology and rare variants in the uRPL etiology.

Concurrent of compound heterozygous variant of a novel in-frame deletion and the common hypomorphic haplotype in TBX6 and inherited 17q12 microdeletion in a fetus

BackgroundTBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound heterozygosity of disruptive variants in trans with a common hypomorphic risk haplotype (T-C-A) in the TBX6 gene contribute to 10% of congenital scoliosis (CS) cases. The deletion of chromosome 17q12 is a rare cytogenetic abnormality, which often leads to renal cysts and diabetes mellitus. However, the affected individuals often exhibit clinical heterogeneity and incomplete penetrance.MethodsWe here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6.ResultsWES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman.ConclusionsThis study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.