scholarly journals Molecular Screening of PROKR2 Gene in Girls with Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Precocious Puberty ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Minor Allele ◽  
Fisher Exact Test ◽  
Molecular Screening ◽  
First Case ◽  
A Minor

Abstract Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017 a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5-year-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) in order to identify possible alterations in PROKR2. Methods: We analyzed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels >0.3 IU/L or peak-LH>5IU/L after stimulation, negative for MKRN3 mutations. The Fisher exact test was used to compare allele frequency of polymorphism found to genome aggregation database (gnomAD).Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency similar to that reported in literature. rs3746682 presented a minor allele frequency higher than described in the gnomAD (0.84 in our population vs 0.25 from gnomAD). Conclusions: As for other G-protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Molecular Screening of PROKR2 Gene in Girls with very early Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Minor Allele ◽  
Fisher Exact Test ◽  
Molecular Screening ◽  
First Case ◽  
Exome Aggregation Consortium ◽  
A Minor

Abstract Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017 a first case of central precocious puberty (CPP) caused by heterozygous gain of function mutation in PROKR2 was described in a 3.5-year‐old girl. No other cases have been reported yet. This study performs a molecular screening in girls with “early” onset CPP (breast budding before 6 years of age) in order to identify possible alterations in PROKR2.Methods We analyzed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5UI/L after stimulation, negative for MKRN3 mutations. The Fisher exact test was used to compare allele frequency of polymorphism found to Exome Aggregation Consortium (ExAC) dataset.Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency similar to that reported in literature. rs3746682 presented a minor allele frequency higher than described in The Exome Aggregation Consortium (ExAC) (0.84 in our population vs 0.25 from ExAC).Conclusions As for other G-protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. Methods We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD). Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD). Conclusions As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Molecular Screening of PROKR2 Gene in Girls with Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been describedas cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty(CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-oldgirl. No other cases have been reported yet. This study performs a molecular screening ingirls with early onset CPP (breast budding before 6 years of age) to identify possiblealterations in PROKR2.Methods: We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels >0.3IU/L or peak-LH>5IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD).Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD).Conclusions: As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 donot seem to be a frequent cause of CPP in girls.

Whole Genome Scanning in Aplastic Anemia Indicates That Polymorphisms in CD33 and Other Loci Can Constitute Predisposition Factors in This Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3095-3095
Author(s):  
Bartlomiej P Przychodzen ◽  
Monika Jasek ◽  
Sandra P Smieszek ◽  
Anna Malgorzata Jankowska ◽  
Christine O’Keefe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Minor Allele ◽  
Whole Genome ◽  
Genome Scanning ◽  
A Minor ◽  
Low Prevalence ◽  
The Impact

Abstract While immune mechanisms are involved in the pathogenesis of idiopathic aplastic anemia (AA), the discovery of telomerase machinery mutations in a minority of patients with a not easily discernable phenotype illustrates that polygenic, low penetrance traits may exist and contribute to increased risk for this disease in certain individuals. However, due to the impact of exogenous factors and the low prevalence of AA, this disease is not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies such as SNP arrays (SNP-A), large scale investigations in various disorders have been conducted. We have applied SNP-A to conduct the first GWAS in AA with the goal to identify possible low prevalence genetic variants that contribute to the pathogenesis and explain individual disease risk. We have studied 128 patients with AA and PNH and 119 controls using SNP-A. Affymetrix GeneChip 6.0 (924644 SNP probes covering most known LD blocks) was designed to capture 67%–89% of SNP variation among Caucasians. Following exclusion of SNPs with a call rate of <95%, and those with serious violation of Hardy-Weinberg equilibrium, single allele χ2 statistics for all autosomal markers was performed. For the purpose of this study, SNPs with a minor allele frequency (MAF) <10% and p<0.001 after false discovery rate correction were selected, whereby all SNP were used multi-variedly to predict disease association. Application of the Benjamini-Hochberg strategy more closely reflects complex polygenic traits. The top 85 SNPs (ranked by p-value) were chosen for further analysis. Our investigations focused on 5 SNPs which pointed directly to 2 genes or indirectly to informative loci through LD, including CD33 and TCF7. For instance, a minor allele (rs3972624, rs17167302, p<5.69×10−5) of TCF7 is present in a heterozygous and homozygous constellation in patients at 19% and 3% (vs. 3.7% and 0% of controls). TCF7 can bind the enhancer element of TCRα and is preferentially expressed in cells polarized to the Th1 direction. Polymorphism in the TCF7 gene was reported to be associated with type-1 diabetes, which is a disease with dominating Th1 phenotype. Furthermore, TCF7 is a member of the WNT-β-catenin LEF1/TCF7 pathway with a known role in the maintenance of hematopoietic stem cells. Increased minor allele frequency of rs1803254, rs9676731, rs1501449 in the CD33 locus, already part of a LD block, was homozygous and heterozygous at 3.4% vs. 0% and 24.8% vs. 7.9% (p<7.1×10−5) in patients and controls, respectively. To further confirm this genetic link, we have investigated the frequency of this polymorphism using an independent set of controls (N=1658) and an overlapping group of patients (12 additional and 52 6.0 array-studied patients). This analysis provided technical validation of genotyping calls in 100% repetitive samples and confirmed the allelic frequency of this SNP in AA at 14.9% vs. 4.5% in controls (p<4×10−5). This marker (rs1803254), representing itself as a genetic proxy, points toward an informative locus in exon 7 of the CD33 gene. CD33 is cell-surface glycoprotein that is specific for the myeloid lineage. It was reported that expression frequencies of CD33 were significantly reduced in AA bone marrow, in comparison to normal bone marrow. In vitro experiments indicate that CD33 may act as an inhibitory receptor and anti-CD33 antibody can induce apoptosis in AML cells. In sum, our study constitutes one of highest resolution investigations into susceptibility loci in AA. Our results point towards a number of interesting genetic disease-associations in AA which are currently being investigated through sequencing of corresponding loci in larger independent cohorts of patients.

scholarly journals Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome

2018 ◽  
Vol 29 (12) ◽  
pp. 2809-2819 ◽  
Author(s):  
Fengxiao Bu ◽  
Yuzhou Zhang ◽  
Kai Wang ◽  
Nicolo Ghiringhelli Borsa ◽  
Michael B. Jones ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Minor Allele ◽  
Complement Protein ◽  
Predisposing Factor ◽  
Uremic Syndrome ◽  
A Minor ◽  
Coding Variants

BackgroundGenetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous.Methods We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggregation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant.ResultsWe found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE, and VTN genes. The majority of the significance is contributed by variants with a minor allele frequency of <0.1%. Disease-related variants tend to occur in specific complement protein domains of FH, CD46, and C3. We observed no enrichment for multiple rare coding variants in gene-gene combinations.ConclusionsIn known aHUS-associated genes, variants with a minor allele frequency >0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available. VTN, which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS-associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS.

scholarly journals Minor allele frequency thresholds dramatically affect population structure inference with genomic datasets

2017 ◽  
Author(s):  
Ethan Linck ◽  
C.J. Battey
Keyword(s):  
Population Structure ◽  
Best Practices ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Minor Allele ◽  
Data Matrix ◽  
Rigorous Analysis ◽  
Total Size ◽  
Model Based ◽  
A Minor

AbstractOne common method of minimizing errors in large DNA sequence datasets is to drop variable sites with a minor allele frequency below some specified threshold. Though widespread, this procedure has the potential to alter downstream population genetic inferences and has received relatively little rigorous analysis. Here we use simulations and an empirical SNP dataset to demonstrate the impacts of minor allele frequency (MAF) thresholds on inference of population structure. We find that model-based inference of population structure is confounded when singletons are included in the alignment, and that both model-based and multivariate analyses infer less distinct clusters when more stringent MAF cutoffs are applied. We propose that this behavior is caused by the combination of a drop in the total size of the data matrix and by correlations between allele frequencies and mutational age. We recommend a set of best practices for applying MAF filters in studies seeking to describe population structure with genomic data.

Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism

2008 ◽  
Vol 99 (11) ◽  
pp. 905-908 ◽  
Author(s):  
Bettina Kulle ◽  
Beate Luxembourg ◽  
Katja Blouin ◽  
Michael Spannagl ◽  
Edelgard Lindhoff-Last ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Factor Viii ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Density Lipoprotein ◽  
Minor Allele ◽  
Chromosome 8 ◽  
Trend Test ◽  
Causal Polymorphism ◽  
A Minor

SummaryA suggestive locus on chromosome 8 could be shown to be associated with familial high factor VIII (FVIII) levels in venous thromboembolism. The ADAMDEC 1 gene is a candidate expressing an ectodomain sheddase. However, the ectodomain of the clearance receptor for FVIII, the low-density lipoprotein receptor-related protein (LRP), is subject to proteolysis by metalloproteases like ADAMDEC1. Other LRP-interacting proteins are lipoprotein lipase (LPL) and t-PA. For an association study, 165 thrombotic patients with high FVIII levels (from the MAISTHRO, i.e. Main-Isar-thrombosis register) were included. All patients with known causes for high FVIII levels had been previously excluded. The patients were compared with 214 healthy blood donors. Polymorphisms with usually a minor allele frequency > 5 %, i.e. 24 SNPs and two insertion/deletion polymorphisms of LPL gene, eight SNPs of the t-PA gene, and five SNPs of the ADAMDEC1 gene, were analyzed. Haplotype differences were calculated using PHASE. A new polymorphism in intron 7 of the t-PA gene with a minor allele frequency of 2.2% was identified. Analysis of each SNP by the Cochrane-Armitage trend test did not show any significant association between genotype and disease status. Interestingly, the ADAMDEC1 haplotype (rs12674766, rs10087305, rs2291577, rs2291578, rs3765124) differed between cases and controls (p=0.04). In particular, the TGTGG haplotype showed a difference. In conclusion, the ADAMDEC 1 haplotype may indicate an underlying mechanism for high FVIII levels. The only moderate linkage disequilibrium may be due to a possible causal polymorphism in distant introns or the promoter region against a polygenic background.

scholarly journals Cancer Protection Elicited by a Single Nucleotide Polymorphism Close to the Adrenomedullin Gene

2013 ◽  
Vol 98 (4) ◽  
pp. E807-E810 ◽  
Author(s):  
Sonia Martínez-Herrero ◽  
Alfredo Martínez
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Direct Sequencing ◽  
Minor Allele ◽  
Cardiac Insufficiency ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Healthy Donors ◽  
A Minor

Context: The risk of developing cancer is regulated by genetic variants, including polymorphisms. Characterizing such variants may help in developing protocols for personalized medicine. Objective: Adrenomedullin is a regulatory peptide involved in cancer promotion and progression. Carriers of a single nucleotide polymorphism (SNP) in the proximity of the adrenomedullin gene have lower levels of circulating peptide. The aim of the present work was to investigate whether carriers of this SNP (rs4910118) are protected against cancer. Design: This was a retrospective study. DNA samples were obtained from the Carlos III DNA National Bank (University of Salamanca, Salamanca, Spain). Setting: Samples represent a variety of donors and patients from Spain. Patients or Other Participants: DNA from patients with breast cancer (n = 238), patients with lung cancer (n = 348), patients with cardiac insufficiency (n = 474), and healthy donors of advanced age (n = 500) was used. Interventions: All samples were genotyped using double-mismatch PCR, and confirmation was achieved by direct sequencing. Main Outcome Measures: The minor allele frequency was calculated in all groups. The Pearson χ2 was used to compare SNP frequencies. Results: Of 1560 samples, 14 had the minor allele, with a minor allele frequency in healthy donors of 0.90%. Patients with cancer had a statistically significantly lower frequency than healthy donors (odds ratio = 0.216, 95% confidence interval = 0.048–0.967, P = .028). Conclusions: Carriers of the minor allele have a 4.6-fold lower risk of developing cancer than homozygotes for the major allele. Knowledge of the rs4910118 genotype may be useful for stratifying patients in clinical trials and for designing prevention strategies.

P–541 Identification of novel variants and candidate genes in women with familial idiopathic premature ovarian failure using whole-exome sequencing

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
R Morale. Sabater ◽  
B Lledo ◽  
J A Ortiz ◽  
F Lozano ◽  
A Bernabeu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Allele Frequency ◽  
Whole Exome Sequencing ◽  
Minor Allele Frequency ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Failure ◽  
Minor Allele ◽  
Whole Exome

Abstract Study question Is it possible to identify a genetic cause of familial premature ovarian failure (POF) with whole-exome sequencing (WES)? Summary answer Whole-exome sequencing is the most efficient strategy to identify probably pathogenic mutations in different genes in pathologies of polygenic etiology such as premature ovarian failure. What is known already Premature ovarian failure is the loss of ovarian function before the age of 40, and it is a common cause of infertility in women. This pathology has a heterogeneous etiology. Some chromosomal and genetic alterations have been described, and could explain approximately 20% of cases. However, in most patients the origin remains unknown. Recent studies with next-generation sequencing (NGS) have identified new variants in candidate genes related with premature ovarian insufficiency (POI) or premature ovarian failure (POF). These genes are not only involved in processes such as folliculogenesis, but also with DNA damage repair, homologous recombination, and meiosis. Study design, size, duration Fourteen women, from 7 families, affected by idiopathic POF were included in the study from October 2019 to September 2020. Seven POF patients were recruited when they came to our clinic to undergo assisted reproductive treatment. In the anamnesis, it was found that they had relatives with a diagnosis of POF, who were also recruited for the study. The inclusion criteria were amenorrhea before 38 years old and analytical and ultrasound signs of ovarian failure. Participants/materials, setting, methods WES was performed using TrusightOne (Illumina®). Sequenced data were aligned through BWA tool and GATK algorithm was used for SNVs/InDel identification. VCF files were annotated using Variant Interpreter software. Only the variants shared by each family were extracted for analysis and these criteria were followed: (1) Exonic/splicing variants in genes related with POF or involved in biological ovarian functions (2) Variants with minor allele frequency (MAF) ≤0.05 and (3) having potentially moderate/strong functional effects. Main results and the role of chance Seventy-nine variants possibly related with the POF phenotype were identified in the seven families. All these variants had a minor allele frequency (MAF) ≤0.05 in the gnomAD database and 1000 genomes project. Among these candidate variants, two were nonsense, six splice region, one frameshift, two inframe deletion and 68 missense. Thirty-two of the missense variants were predicted to have deleterious effects by minimum two of the four in silico algorithms used (SIFT, PolyPhen–2, MutationTaster and PROVEAN). All variants were heterozygous, and all the families carried three or more candidate variants. Altogether, 43 probably damaging genetic variants were identified in 39 genes expressed in the ovary and related with POF/POI or linked to ovarian physiology. We have described genes that have never been associated to POF pathology, however they may be involved in key biological processes for ovarian function. Moreover, some of these genes were found in two families, for example DDX11, VWF, PIWIL3 and HSD3B1. DDX11 may function at the interface of replication-coupled DNA repair and sister chromatid cohesion. VWF gene is suggested to be associated with follicular atresia in previous studies. PIWIL3 functions in development and maintenance of germline stem cells, and HSD3B1 is implicated in ovarian steroidogenesis. Limitations, reasons for caution Whole-exome sequencing has some limitations: does not cover noncoding regions of the genome, it also cannot detect large rearrangements, copy-number variants (large deletions/duplications), mosaic mutations, mutations in repetitive or high GC rich regions and mutations in genes with corresponding pseudogenes or other highly homologous sequences. Wider implications of the findings: WES has previously shown to be an efficient tool to identify genes as cause of POF, and has demonstrated the polygenic etiology. Although some studies have focused on it, and many genes are identified, this study proposes new candidate genes and variants, having potentially moderate/strong functional effects, associated with POF. Trial registration number Not applicable

MO275RARE VARIANTS OF COMPLEMENT FACTOR H AND THROMBOMODULIN ARE OVER-REPRESENTED IN A COHORT OF SEVERE IGA NEPHROPATHY PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Nicolas Maillard ◽  
Veronique Fremeaux Bacchi ◽  
Paula Vieira-Martins ◽  
Perrine Jullien ◽  
Eric Alamartine ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Allele Frequency ◽  
Rare Variant ◽  
Minor Allele Frequency ◽  
Rare Variants ◽  
Regulatory Genes ◽  
Factor H ◽  
Minor Allele ◽  
Risk Haplotype ◽  
Complement Factor

Abstract Background and Aims IgA nephropathy is the most frequent primary glomerulonephritis leading to end stage renal disease (ESRD) in about 30% of cases within 20 years after diagnosis. Complement activation through alternative and lectin pathways has been described to impact the pathogeny of the disease. We hypothesized in this study that rare variants of alternative pathways regulatory genes could be overrepresented and could play a role at initiating the disease and could harm the prognosis of IgA Nephropathy. Method Patients with biopsy proven IgA nephropathy with markers of severity comprising an evolution through ESRD and/or a proteinuria &gt;0.5g/day with available DNA sample were included. All coding sequences of CFH, CFI, MCP, C3, Factor B THBD and CFHR5 genes were analyzed by next generation sequencing. We defined a variant as rare when its minor allele frequency was below 0.1% in the general population. Frequencies were compared to a French volonteers cohort (n=80) and a European large cohort (n=503) Results We screened 128 patients with IgA N, with following characteristics at diagnosis: median age 42.4 yo, proteinuria (median) 1.4g/day, hypertension 66%, median eGFR 48.7 mL/min/1.73m². The median follow-up was 99 months and 58% of patients progressed to ESRD. We identified rare variants with MAF&lt;0.1% in 10.2 % (n=13) including 1 patient with two rare variants. The functional consequences of the 12 out the 14 variants are unknown. Two variants in CFH are located in function domains and are pathogenic. Patients with IgA N have high rates of rare variants in CFH (n=9/128 ; 7 %) versus normal controls (n=9/503 ; 1.8%) (p=0.004); Pathogenic Variants with minor allele frequency &lt;0.1% in CFH were found in 2 IgA N (2 out of 128, 1.5%) versus 1 European controls (1 out of 503) In total, 11 % (14/128), 3.8 % (5/128) and 0.8 % (1/128) of the 128 patients were homozygous for the at-risk haplotype MCP ggaac, CFH tgtgt or both, respectively (versus 6.2 % (5/80), 3.8 % (3/80) and 0% in the controls) 6 patients carried the pathogenic variant in THDM gene p.Ala43Thr (6/128) versus 5 in 508 controls population (p=0.01). No difference in term of hypertension, proteinuria, eGFR, Oxford classification, vascular score at diagnosis was noticed between patients without any rare variant compared to patients with at least one rare variant. The progression through ESRD was not different between groups. Conclusion In this cohort of Caucasian IgA nephropathy patients, rare variants of CFH and THBD were found significantly overrepresented compared to a French and European control cohort. Rare variants of alternative pathway regulatory genes were not associated with particular severity or prognosis.

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