Monogenic Genes Research Articles

A narrative review of monogenic disorders causing nephrolithiasis and chronic kidney disease.

The incidence and prevalence of genetic diseases associated with chronic kidney disease (CKD) have been increasing over the last decades. To identify the monogenic causes of kidney stone disorders linked to CKD, a comprehensive literature review was conducted to identify monogenic genes causing nephrolithiasis and CKD. Among 41 identifiable monogenic causes of nephrolithiasis the following diseases primary hyperoxaluria familial hypomagnesemia with hypercalciuria and nephrocalcinosis, cystinuria; Dent disease, adenine phosphoribosyltransferase deficiency, Lesch-Nyhan syndrome, and idiopathic Infantile hypercalciuria have been linked to CKD and may progress to end-stage kidney disease (ESKD). Autosomal dominant hypocalcemia and Bartter syndrome (BS) are also hereditary kidney diseases that can cause urolithiasis but are rarely associated with CKD. A few BS type III can be complicated with CKD. A substantial number of kidney stone patients with genetic disorders progress to CKD. Genetic diagnosis should be initiated in all children presenting with kidney stones.

Expanded phenotypic spectrum in MODY 5 patients with 17q12 deletion syndrome: experience from an Indian tertiary care hospital.

To study the clinical and genotypic spectrum of patients with HNF-1ß deletions (MODY 5) at a tertiary care hospital. This study included four patients from the Department of Endocrinology at Sher-i-Kashmir Institute of Medical Sciences Srinagar with a strong clinical suspicion of MODY 5. Genetic analysis, including a monogenic gene panel comprising 78 genes associated with MODY and other similar forms of monogenic diabetes, was done. Dosage analysis of HNF 1B by Multiplex Ligand-dependent Probe Amplification (MLPA) was performed. The mean age of patients was 22.25 years with a male-to-female ratio of 3:1. Associated phenotypic features included neurodevelopmental disorder in all four patients, insulin resistance in two patients (2/4) and alopecia in three patients (3/4). One patient had clinical and biochemical hyperandrogenism. All patients had renal malformations, and one patient had a Mullerian anomaly. Family history was present in 1 patient. All patients had pancreatic abnormalities, the most common type being dorsal agenesis of the pancreas (3/4), followed by annular pancreas (1/4). All patients had a genetic deletion of the gene HNF1B on chromosome 17 with a deletion interval of (?_37686431)_(37745059_?), (?_37687281)-(37744884_?), comprising exons 1 to 9. It is imperative to maintain a high index of suspicion for MODY 5 in patients presenting with renal anomalies and diabetes, even in the absence of a family history. Early identification allows for screening family members and ensures a comprehensive approach to identifying and managing other abnormalities in these patients.

Monogenic gene therapy for glaucoma and optic nerve injury.

Monogenic gene therapy for glaucoma and optic nerve injury.

What Causes Premature Coronary Artery Disease?

This review provides an overview of genetic and non-genetic causes of premature coronary artery disease (pCAD). pCAD refers to coronary artery disease (CAD) occurring before the age of 65years in women and 55years in men. Both genetic and non-genetic risk factors may contribute to the onset of pCAD. Recent advances in the genetic epidemiology of pCAD have revealed the importance of both monogenic and polygenic contributions to pCAD. Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with atherosclerotic pCAD. However, clinical overreliance on monogenic genes can result in overlooked genetic causes of pCAD, especially polygenic contributions. Non-genetic factors, notably smoking and drug use, are also important contributors to pCAD. Cigarette smoking has been observed in 25.5% of pCAD patients relative to 12.2% of non-pCAD patients. Finally, myocardial infarction (MI) associated with spontaneous coronary artery dissection (SCAD) may result in similar clinical presentations as atherosclerotic pCAD. Recognizing the genetic and non-genetic causes underlying pCAD is important for appropriate prevention and treatment. Despite recent progress, pCAD remains incompletely understood, highlighting the need for both awareness and research.

Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis.

More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71mg/mg at 26weeks, and had lower serum albumin levels of 13.13 ± 1.34g/l at 30weeks. Littermate control mice had urinary ACR mean values of 0.03mg/mg and serum albumin values of 22.89 ± 0.34g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS.

A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases.

With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).

Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes

Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations.

The Rare and Atypical Diabetes Network (RADIANT) Study: Design and Early Results.

The Rare and Atypical Diabetes Network (RADIANT) will perform a study of individuals and, if deemed informative, a study of their family members with uncharacterized forms of diabetes. The protocol includes genomic (whole-genome [WGS], RNA, and mitochondrial sequencing), phenotypic (vital signs, biometric measurements, questionnaires, and photography), metabolomics, and metabolic assessments. Among 122 with WGS results of 878 enrolled individuals, a likely pathogenic variant in a known diabetes monogenic gene was found in 3 (2.5%), and six new monogenic variants have been identified in the SMAD5, PTPMT1, INS, NFKB1, IGF1R, and PAX6 genes. Frequent phenotypic clusters are lean type 2 diabetes, autoantibody-negative and insulin-deficient diabetes, lipodystrophic diabetes, and new forms of possible monogenic or oligogenic diabetes. The analyses will lead to improved means of atypical diabetes identification. Genetic sequencing can identify new variants, and metabolomics and transcriptomics analysis can identify novel mechanisms and biomarkers for atypical disease.

Use of whole-exome sequencing to identify novel monogenic gene mutations and genotype-phenotype correlations in Chinese Han children with urolithiasis.

The incidence of urolithiasis (UL) in children has been increasing. Although the pathogenesis of pediatric UL is controversial and remains unclear, multiple monogenic causes of UL have been identified. We aim to investigate the prevalence of inherited UL causes and explore the genotype-phenotype correlation in a Chinese pediatric group. In this study, we analyzed the DNA of 82 pediatric UL patients using exome sequencing (ES). The data of metabolic evaluation and genomic sequencing were subsequently analyzed together. We detected 54 genetic mutations in 12 of 30 UL-related genes. A total of 15 detected variants were described as pathogenic mutations, and 12 mutations were considered likely pathogenic. Molecular diagnoses were made in 21 patients with pathogenic or likely pathogenic variants. Six novel mutations that were not previously reported were identified in this cohort. Calcium oxalate stones were detected in 88.9% cases (8/9) with hyperoxaluria-related mutations, while 80% of individuals (4/5) with cystinuria-causing defects were diagnosed with cystine stones. Our study highlights the significant genetic abnormalities in pediatric UL and demonstrates the diagnostic power of ES for screening patients with UL.

MP24-12 ASSOCIATION OF RARE MONOGENIC VARIANTS WITH DIAGNOSIS OF BPH USING WHOLE EXOME SEQUENCING IN THE UK BIOBANK

You have accessJournal of UrologyCME1 Apr 2023MP24-12 ASSOCIATION OF RARE MONOGENIC VARIANTS WITH DIAGNOSIS OF BPH USING WHOLE EXOME SEQUENCING IN THE UK BIOBANK Clark Judge, David Nusbaum, Jun Wei, Zhuqing Shi, Andrew Rifkin, S. Lilly Zheng, Brian Helfand, Alexander Glaser, and Jianfeng Xu Clark JudgeClark Judge More articles by this author , David NusbaumDavid Nusbaum More articles by this author , Jun WeiJun Wei More articles by this author , Zhuqing ShiZhuqing Shi More articles by this author , Andrew RifkinAndrew Rifkin More articles by this author , S. Lilly ZhengS. Lilly Zheng More articles by this author , Brian HelfandBrian Helfand More articles by this author , Alexander GlaserAlexander Glaser More articles by this author , and Jianfeng XuJianfeng Xu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003249.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a common condition that leads to bothersome lower urinary tract symptoms. Polygenic heritability of BPH has been demonstrated using genetic risk scores derived from common single nucleotide polymorphisms, but rare monogenic gene mutations associated with BPH have not been well described. The objective of this study was to determine the impact of rare monogenic variants on the development of BPH. METHODS: A total of 83,631 men from the UK Biobank (UKB) with whole exome sequencing data were included and categorized based on ICD10 diagnosis of BPH (N40). Of men with BPH, 9,697 were further characterized as undergoing transurethral resection of prostate (TURP). The robust SKAT-O, a novel gene-based analysis of pathogenic/likely pathogenic mutations that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment and genetic background. RESULTS: Nineteen candidate genes were identified as associated with BPH in 9,697 cases compared to 73,934 controls at p<0.001 using SKAT-O (Table). However, none of these associations was significant after adjusting for multiple testing (FDR<0.05). For most of these genes, higher carrier rates in patients undergoing TURP was also found. CONCLUSIONS: In this large study of nearly 84,000 men, several candidate genes were identified. Confirmation in independent study populations is required. Identification of monogenic gene mutations associated with BPH may advance our understanding of disease etiology and identify potential therapeutic targets. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e322 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Clark Judge More articles by this author David Nusbaum More articles by this author Jun Wei More articles by this author Zhuqing Shi More articles by this author Andrew Rifkin More articles by this author S. Lilly Zheng More articles by this author Brian Helfand More articles by this author Alexander Glaser More articles by this author Jianfeng Xu More articles by this author Expand All Advertisement PDF downloadLoading ...

MP41-12 ASSOCIATION OF KIDNEY CANCER WITH BOTH NOVEL AND REPORTED MONOGENIC GENE MUTATIONS: RESULTS OF WHOLE EXOME SEQUENCING IN THE UK BIOBANK

You have accessJournal of UrologyCME1 Apr 2023MP41-12 ASSOCIATION OF KIDNEY CANCER WITH BOTH NOVEL AND REPORTED MONOGENIC GENE MUTATIONS: RESULTS OF WHOLE EXOME SEQUENCING IN THE UK BIOBANK Jun Wei, Kristian Novakovic, Zhuqing Shi, Andrew Rifkin, S. Lilly Zheng, Brian Helfand, and Jianfeng Xu Jun WeiJun Wei More articles by this author , Kristian NovakovicKristian Novakovic More articles by this author , Zhuqing ShiZhuqing Shi More articles by this author , Andrew RifkinAndrew Rifkin More articles by this author , S. Lilly ZhengS. Lilly Zheng More articles by this author , Brian HelfandBrian Helfand More articles by this author , and Jianfeng XuJianfeng Xu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003279.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Pathogenic mutations in several cancer susceptibility genes have been reported in kidney cancer patients. However, their associations with kidney cancer have not been formally tested in well-characterized case-control studies and using the same sequencing and analytical pipeline. The objective of this study was to systematically evaluate association of kidney cancer with genes in the exome in a well-characterized prospective population-based case-control cohort. METHODS: A total of 187,966 subjects from the UK Biobank (UKB) with whole exome sequencing data were included in the analysis, including 1,217 kidney cancer patients (ICD10 C64). Pathogenic/likely pathogenic (P/LP) mutations were annotated based on criteria of the American College of Medical Genetics. The robust SKAT-O, a novel gene-based analysis that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender and genetic background. RESULTS: Among the 21 previously reported candidate genes, three were statistically significant at P<0.05, including VHL, SDHB, and CHEK2 (Table). In addition, associations with 9 novel genes (at P<0.0001) were found, including ZNF772, PRIMPOL, HES4, MOXD1, KRTAP10-9, ZNF827, ACAN, CDK20, and LRRFIP1. While these associations were only marginally significant after adjusting for multiple testing, they have potential roles in cancer development. For example, ZNF772 is predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity which are all known to be dysregulated in cancer. CONCLUSIONS: Identification of genes that influence kidney cancer may advance our understanding of disease etiology and identify potential therapeutic targets. Using the same sequencing method and mutation annotation pipeline in the largest population-based cohort to date, we confirmed several previously reported genes and identified several novel candidate genes for their association with kidney cancer. Confirmation in independent study populations is required for these novel candidate genes. Source of Funding: None. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e559 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jun Wei More articles by this author Kristian Novakovic More articles by this author Zhuqing Shi More articles by this author Andrew Rifkin More articles by this author S. Lilly Zheng More articles by this author Brian Helfand More articles by this author Jianfeng Xu More articles by this author Expand All Advertisement PDF downloadLoading ...

5558131 GENETICS OF IRANIAN ALPHA THALASSEMIA PATIENTS; COMPREHENSIVE ORIGINAL STUDY

Background: Alpha thalassemia is the most prevalent monogenic gene disorder in the world and especially in Mediterranean countries. In the current hematological phenotype of patients with different genotypes, and also the effect of missense mutations on the protein function and stability were evaluated in a large cohort study. Methods: One thousand five hundred and and sixty subjects were participated in the study and divided into two groups; 259 normal subjects and 1301 alpha thalassemia carriers. Genomic DNA was extracted and analyzed using ARMS PCR, Multiplex Gap and direct sequencing. The effects of single nucleotide change on the protein function and stability were predicted by free available databases of human polymorphisms. Results: Sixty-three different genotypes were seen in the patients. The more prevalent was heterozygote form of -α3.7 (41.4%) followed by -α3.7 homozygote(11.6%) and - -MED(3.8%). The significant differences were seen in mean hemoglobin level [F=20.5, p<0.001] between the Alpha globin genotypes, when adjusted for gender. Moreover, 28 different mutations were found in our study. A significant relationship was seen between ethnicity and the alpha globin mutation frequency X2 (df;8) = 38.36, p <0.0001). Conclusion: Different genotypes could be displayed as different phenotypes. The mutation frequency distributions in our region is different from other parts of Iran. Significant differences are seen in the spectrum of mutation frequency between various ethnicity. Finally, some missense mutations maybe did not considerably effect on the proteins and could be a neutral mutations. Keywords: Alpha Thalassemia, Genotype, Phenotype, Southwest of Iran

Association of Reported Candidate Monogenic Genes With Lung Cancer Risk

Introduction/BackgroundPublished studies on association of germline monogenic genes and lung cancer risk were inconsistent. Our objective is to assess the validity of reported candidate monogenic genes for their association with lung cancer. Materials and MethodsA systematic review of published papers prior to August 2022 was performed first to identify all genes where germline mutations were associated with lung cancer risk. We then performed a confirmation study in 2,050 lung cancer cases and 198,553 controls in the UK Biobank (UKB). Germline mutations of these genes were identified from sequencing data and annotated using The American College of Medical Genetics criteria. The robust SKAT-O, a gene-based analysis that properly controls for false positives due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, and genetic background. ResultsThe systematic review identified 12 genes that were statistically significantly associated with lung cancer risk in at least one study (P < .05), including ATM, BLM, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, MSH6, PMS1, RAD51C, RAD51D, and TP53. When pathogenic/likely pathogenic mutations were aggregated within each gene, the association was confirmed for ATM (P = 4.47E-4) at the study-wise significance level (P < .0042, Bonferroni correction for 12 tests). Suggestive evidence of association was found for 2 other genes, BRCA2 (P = .007) and TP53 (P = .03). Among these 3 genes, the lung cancer risks range from 1.95 (BRCA2) to 5.28 (TP53). ConclusionThis study provides statistical evidence for association of previously reported genes and lung cancer risk and has clinical utility for risk assessment and genetic counseling.

Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort.

To evaluate which of previously reported monogenic genes are associated with increased bladder cancer risk, we reviewed published papers on associations of genes and bladder cancer risk and performed a confirmation study of these genes in a large population-based cohort. A systematic review of published papers prior to June 2022 was performed first to identify all genes where germline mutations were associated with bladder cancer risk. The associations of these candidate genes with bladder cancer risk were then tested among 1695 bladder cancer cases and 186 271 controls in the UK Biobank (UKB). The robust SKAT-O, a gene-based analysis that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, smoking status, and genetic background. The systematic review identified nine genes that were significantly associated with bladder cancer risk in at least one study (p< 0.05), including MUTYH, MSH2, MSH6, MLH1, ATM, BRCA2, ERCC5, TGFB1 and CHEK2. When pathogenic/likely pathogenic mutations were aggregated within each gene, the association was confirmed for three genes in the UKB at p< 0.0056 (Bonferroni correction for nine tests), including CHEK2, ATM and BRCA2, all also known to be associated with hereditary breast cancer. Suggestive evidence of association was found for two other genes, including MLH1 (p= 0.006) and MSH2 (p= 0.007), both known to be associated with Lynch syndrome. Among these five genes, the bladder cancer risks range from 1.60 (ATM) to 4.88 (MLH1), and mutation carrier rates in cases range from 0.06% (MSH2) to 2.01% (CHEK2). This study provides statistical evidence for association of previously reported genes and bladder cancer risk and has clinical utility for risk assessment and genetic counselling.

Higher Waist Hip Ratio Genetic Risk Score Is Associated with Reduced Weight Loss in Patients with Severe Obesity Completing a Meal Replacement Programme

Background: A better understanding of the influence of genetic factors on the response to lifestyle interventions in people with obesity may allow the development of more personalised, effective and efficient therapeutic strategies. We sought to determine the influence of six obesity-related genetic risk scores on the magnitude of weight lost by patients with severe obesity who completed a dietary intervention. Methods: In this single-centre prospective cohort study, participants with severe and complicated obesity who completed a 24-week, milk-based meal replacement programme were genotyped to detect the frequency of common risk alleles for obesity and type 2 diabetes-related traits. Genetic risk scores (GRS) for six of these traits were derived. Participants with a potentially deleterious monogenic gene variant were excluded from the analysis. Results: In 93 patients completing the programme who were not carrying a known obesity-related gene mutation, 35.5% had diabetes, 53.8% were female, mean age was 51.4 ± 11 years, mean body mass index was 51.5 ± 8.7 and mean total weight loss percent at 24 weeks was 16 ± 6.3%. The waist-hip ratio (WHR) GRS was inversely associated with percentage total weight loss at 24 weeks (adjusted β for one standard deviation increase in WHR GRS -11.6 [-23.0, -0.3], p = 0.045), and patients in the lowest tertile of WHR GRS lost more weight. Conclusions: Patients with severe and complicated obesity with a genetic predisposition to central fat accumulation had less weight loss in a 24-week milk-based meal replacement programme, but there was no evidence for influence from the five other obesity-related genetic risk scores on the response to dietary restriction.

OA30 Genetic analysis of whole exome sequencing in a cohort of children with refractory JIA reveals genetic risk factors for rare juvenile diseases

Introduction/BackgroundJuvenile idiopathic arthritis (JIA) encompasses a group of heterogeneous rheumatic diseases of childhood onset. JIA can result in long term disability and remission is the main goal of treatment. However refractory disease can occur, which is defined as the absence of response to a standard disease therapy. A genetic basis for refractory disease has yet to explored, where deleterious rare variants complicate diagnosis or treatment outcome. This study aimed to investigate, through genetic analysis, whether children with JIA that is refractory carry rare genetic risk factors in genes linked to monogenic diseases.Description/MethodWhole exome sequencing of 99 children with JIA was performed with the Agilent SureSelect Human All ExonV6 kit. All quality control, variant filtering and annotation was performed in Varseq (version 2.2.1). Variants with a read depth <30 and genotype quality <80 were removed. Rarity and pathogenicity filters were then applied to remove variants with an allele frequency >1% (based on ExAC, gnomAD, gnomAD exome, NHLBI and 1KGp phase 3), classified as benign or likely benign on ClinVar, with a CADD PHRED score <15 and a REVEL score >0.7. Variants were annotated if they appeared in a gene from the primary immunodeficiency PanelApp (Martin et al., 2019), in a gene associated with an arthritis phenotype or in a gene that appeared on a paediatric monogenic gene list. The variants were then classified using ACMG guidelines (Richards et al., 2015) and benign, or likely benign, classified variants were removed.Discussion/ResultsA total of 470 variants were identified and we found that 20 out of the 99 children screened were heterozygous for at least one recognised variant in a gene linked to a monogenic disease. Five of these children carried more than one recognised variant linked to monogenic genes. Here we provide a number of illustrative examples: three genes, ADAR, ATP7B and MVK, were prioritised based on prior evidence of associated disease. The variant p.Pro193Ala (gnomAD allele frequency (GAD) 2.2x10-3) of ADAR has previously been deemed pathogenic in a homozygous or compound heterozygous state for Aicardi-Goutières syndrome. Adenosine deaminases (ADARs) catalyse the hydrolytic deamination of adenosine to inosine in dsRNA and is suggested to act as a suppressor of type 1 interferon-stimulated genes. Within ATP7B, two distinct variants were detected; p.Gln1142His (GAD 1.6x10-5) and p.Ile1148Thr (GAD 4.0x10-5) have previously been reported as pathogenic, in combination with a third variant, for Wilson’s disease and were carried by one individual in this cohort. ATP7B encodes copper-transporting ATPase 2, which supplies copper to ceruloplasmin. Variant p.Val377Ile (GAD 1.6x10-3) of MVK was detected in eight individuals in this cohort, interestingly five of these individuals also carried at least one HLA-DRB1 stop-gained variant. This MVK mutation has been confirmed as pathogenic in a homozygous or compound heterozygous state for mevalonate kinase deficiency. MVK converts mevalonic acid into mevalonate-5-phosphate in the cholesterol synthesis pathway. Additionally, two stop-gained loss of function HLA-DRB1 variants, p.Tyr107Ter and p.Gln125Ter, were detected in five and 20 individuals, respectively, in this cohort. HLA-DRB1 is a recognised susceptibility locus for JIA.Key learning points/ConclusionScreening of a cohort of 99 children with JIA that have refractory disease has revealed that individuals carry deleterious variants in genes linked to monogenic forms of disease. These results highlight that the genetic basis for refractory disease needs to be further investigated. Carrying additional genetic risk factors to disease may complicate disease outcome and genetic screening of children with refractory JIA may improve treatment outcome in the future.

Fine mapping of a recessive leaf rust resistance locus on chromosome 2BS in wheat accession CH1539.

The online version contains supplementary material available at 10.1007/s11032-022-01318-4.

Segregation Analysis of SSR Markers and Phenotypic Performances of Four Soybean F2 Populations Based on Morphological Characters and SSR Markers

&lt;p&gt;The role of molecular markers in variety development is very important in increasing selection efficiency through analysis of segregation patterns for subsequent populations. The aims of this study were to analyze patterns of soybean F2 population segregation using SSR markers and morphological characters and analyze phenotypic performances of four soybean F2 populations. Each F2 genotype was evaluated molecularly and phenotypically. The SSR markers and qualitative phenotypic traits, i.e. flower, hypocotyle, and pubescent color segregation ratios, were analyzed using Chi-square tests and the normality of quantitative phenotypic data was done using Liliefors test. Results showed that SSR markers segregated in Mendelian fashion, with a ratio of 1:2:1 of codominant SSR marker, in three F2 populations (Grobogan × Introduksi 10, Grobogan × Introduksi 13, and Biosoy 1 × Introduksi 10). Meanwhile, in F2 population Grobogan × Introduksi 12 the SSR markers did not demonstrate a 1:2:1 segregation ratio. However, that population skewed toward alleles from Grobogan. Phenotypic data of flower, hypocotyle, and pubescent colors were segregated in a 3:1 ratio of dominant monogenic genes for populations Grobogan × Introduksi 13 and Biosoy 1 × Introduksi 10. Liliefors analysis showed that quantitative characters, such as plant height, pod number/plant, seed yield/plant, and 100-seed weight observed in the F2 populations showed normal distribution as expected since the characters are controlled by many genes. Three of the four F2 populations resulted from this study can be used for genetic mapping study and for breeding programs of aluminum-toxicity, flooding, and drought tolerance characters in soybean.&lt;/p&gt;

Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

O-147 Genomic analyses in 101,127 UK women show that previously reported monogenic genes are not common causes of premature ovarian insufficiency

Abstract Study question What is the penetrance of variants in previously reported genes for premature ovarian insufficiency (POI) in the general population? Summary answer Heterozygous genetic variants in previously reported monogenic genes are not a common, highly penetrant cause of POI. What is known already Premature ovarian insufficiency (POI), defined as menopause before 40, has been associated with variants in over 70 genes. However, the evidence to support the causality of individual genetic variants varies between studies. As genomic data becomes more accessible, it is essential to ascertain the penetrance of variants in the absence of family history information. We identified 75 genes associated with POI from the literature, including family segregation studies, consanguineous pedigrees and cohort analyses of whole-exome/targeted sequencing data. Functional evaluation was also available for many of the genes. Study design, size, duration We used data from 101,127 females of European ancestry in the UK Biobank, to study the role of previously reported monogenic causal genes on ovarian function. We tested the association of 301 previously reported variants with POI and ANM, plus more than 2.5 million rare variants which were annotated and had not been implicated in POI previously. Genomic variants were tested individually and also combined into a gene burden test. Participants/materials, setting, methods Age at natural menopause (ANM) was derived from self-reported questionnaire data from the age at last menstrual period, excluding those with surgical menopause or taking hormone replacement therapy. POI cases were classified as women with ANM under 40 years (N = 2,213). Linked primary care records were used to identify a clinical cohort of POI cases, including primary amenorrhea (N = 113). Main results and the role of chance All of the previously reported individual variants we identified in our POI cases were also detected in the control group. Moreover, the gene burden tests were not associated with POI or ANM as a quantitative trait. Our results indicate that autosomal dominant causes of POI are rare; a single predicted loss-of-function (LOF) or non-synonymous genetic variant in one of the previously reported genes is generally not pathogenic. Limitations, reasons for caution The penetrance of monogenic disease-causing variants is likely to be lower in population-based cohorts such as UK Biobank than in clinically-ascertained cohorts. Wider implications of the findings Heterozygous LOF or non-synonymous variants in previously reported POI genes should be interpreted with caution and are unlikely to cause POI. The findings have implications for clinicians diagnosing causes of POI. Trial registration number Not applicable