Prevalence Of Pathogenic Variants Research Articles

A Single-Center Retrospective Cohort Study of Genotype–Phenotype Correlation of Osteogenesis Imperfecta in UAE

Abstract Background Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by skeletal fragility. Patients with OI suffer recurrent fractures, limb deformities, and kyphoscoliosis. Multiple extraskeletal manifestations might also be present. Autosomal dominant variants in the COL1A1 or COL1A2 genes account for approximately 90% of cases. Objective The aim of the study was to describe the variant spectrum and genotype–phenotype correlations in patients with OI seen in Tawam Hospital in the UAE. Methods The authors conducted a retrospective chart review for all patients with OI assessed by geneticists at Tawam Hospital from January 2010 to December 2021. They retrieved each patient's baseline characteristics, detailed history and physical examination, laboratory, imaging, and genetic results. Results A total of 40 patients with OI were found and included in this study. The majority (80%) were Emirati, and 57.5% were females. Consanguinity was documented in 24.3%. Thirty-seven patients (92.5%) had positive molecular testing; 28 patients (75.7%) had an autosomal dominant inheritance, and 9 patients (24.3%) had an autosomal recessive inheritance. The majority had missense variants. Four variants were novel. A high prevalence of pathogenic variants in the COL1A1 gene (57%) was found. Patients with variants in the LEPRE1 gene had early and severe phenotypes, while patients with variants in the TMEM38B gene had variable presentations. The majority of patients (85%) had skeletal phenotypes: fractures, bone deformity, scoliosis, and osteopenia. Extraskeletal phenotypes included blue sclera, dentinogenesis imperfecta, hearing loss, and dysmorphic features. Conclusion This study reports the genotype–phenotype correlation of OI patients from the UAE. A high prevalence of pathogenic variants in the COL1A1 gene with OI type IV phenotype was found. Further multicenter more extensive studies are recommended.

Primary mitochondrial disorders and mimics: Insights from a large French cohort.

The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes. Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes. The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases. We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.

Abstract PO5-08-11: Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort

Abstract Background: The Ashkenazi Jewish (AJ) population exhibits a distinctive mutation profile in BRCA1 and BRCA2 (BRCA1/2), characterized by 3 common founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. These 3 mutations are associated with 10% of invasive breast cancer (BC) cases among AJ women. However, the frequency of non-founder pathogenic variants in BRCA1/2 and other BC-related genes in AJ women with BC remains unclear. Methods: This retrospective study included AJ patients diagnosed with stage I-II human epidermal receptor growth factor 2 negative BC between 2004-2022 at the Weill Cornell Breast Center. We collected clinicopathological characteristics and genetic information to determine the frequency of predisposing mutations in BC and non-BC related genes in AJ patients with early BC. We also analyzed the clinicopathological characteristics and outcomes of patients with and without germline mutations in these genes. Results: The study included 232 self-identified AJ patients, with 98% being females. The median age at BC diagnosis was 62 years (IQR: 50-70). Stage I and II cancers accounted for 68% and 32% of cases, respectively. Hormone receptor positivity (HR+) was observed in 71% of patients, while 29% had triple-negative tumors. Genetic testing was performed on 88% (n=203) of the patients, while 5% of patients declined to undergo genetic testing. Among the tested patients, 12% (n=25/203) had pathogenic variants in BRCA1 or BRCA2, with 44% and 16% of these corresponding to the BRCA1 and BRCA2 founder mutations, respectively. Testing beyond BRCA1/2 genes was conducted on 154 patients, and only 6% (n=9/154) were found to have pathogenic variants in CHEK2, while no mutations were detected in other prevalent BC-related genes, including PALB2 and ATM. Fourteen-percent of patients had pathogenic mutations in other genes including APC, CFTR, FH, DIS3L2, FANCC, MUTYH, NF1 and VHL. The frequency of pathogenic BRCA1/2 variants was inversely proportional to the age at BC diagnosis: 50% (n=8/16), 21% (n=8/39), 15% (n=6/40), and 3% (n=3/108) of patients diagnosed at age < 40, 40-49, 50-59, and >60 years, respectively, had a pathogenic variant in either BRCA1 or BRCA2. The frequency of founder mutations varied according to age at diagnosis: 63%, 75%, 17%, and 100% for patients aged < 40, 40-49, 50-59, and >60 years, respectively. Patients with BRCA1/2 mutations exhibited higher-risk clinicopathological features compared to those without mutations, including a higher proportion of high histological grade (88%), and triple-negative tumors (76%). Mastectomy was the primary surgical treatment for 56% and 23% of patients with and without BRCA1/2 mutations, respectively. No difference in disease-free survival was found between patients with and without BRCA1/2 mutations with a median follow up of 3 years (IQR: 1-4). Conclusions: In our cohort, 17% of AJ patients with early BC carried a pathogenic variant in a BC-related gene, with BRCA1/2 being the most commonly affected genes. The proportion of pathogenic variants in BRCA1/2 showed an inverse correlation with the age at BC diagnosis, reaching up to 50% in patients diagnosed under the age of 40. These findings contrast with the lower prevalence of pathogenic variants in BRCA1/2 (38%) reported in the existing literature for this age group. Additionally, 8% of patients had pathogenic variants in other tested cancer genes carrying a genetic predisposition to colorectal cancer (CRC). These findings contribute to our understanding of the genetic landscape of early BC in the AJ population and emphasize the importance of comprehensive genetic testing, particularly among young patients. These results also suggest the need for earlier and more frequent CRC screening in a population of BC patients that may not be adhering to recommended guidelines. Furthermore, our study provides insight into how this genetic landscape may vary when analyzing late-stage BC in women of AJ heritage. Citation Format: Laura Munoz Arcos, Eleonora Nicolò, Maira Pires, Letizia Pontolillo, Leticia Varella, Tessa Cigler, Eleni Andreopolu, Anne Moore, Ashley Schreier, Carlos Munoz-Zuluaga, Lisa Newman, Georgia Syrnioti, Massimo Cristofanilli. Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-11.

Targeted genetic analysis in a cohort of sporadic death from spontaneous rupture of thoracic aortic dissection in Han Chinese population

PurposeThoracic aortic dissection (TAD) is a life-threatening cardiovascular disease that often results in sudden cardiac death (SCD). However, the genetic characteristics of individuals with TAD confirmed at autopsy have been rarely studied. Our objective was to determine the prevalence of pathogenic variants in TAD-associated genes in a cohort of sporadic deaths resulting from spontaneous rupture of TAD and identify relevant genotype-phenotype relationships in Han Chinese population. MethodsWe included sixty-one consecutive sporadic decedents whose primary cause of death was spontaneous rupture of TAD, and performed a whole exome sequencing based strategy comprising 26 known TAD-associated genes. ResultsWe identified 7 pathogenic or likely pathogenic (P/LP) variants in 7 cases (11.48 %) and 22 variants of uncertain significance (VUS) in 22 cases (36.07 %). The FBN1 gene was found to be the major disease-causing gene. Notably, TAD decedents with P/LP variant exhibited significantly earlier mortality. Moreover, we reported for the first time that TAD decedents with P/LP variant had a shorter diagnosis and treatment time. ConclusionOur study investigated the genetic characteristics of TAD individuals confirmed until autopsy in Han Chinese population. The findings enhanced the understanding of the genetic underpinnings of TAD and have significant implications for clinical management and forensic investigations.

Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome

Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. Cross-sectional study. University Research Laboratory. 158 patients with nHH/KS. Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. P/LP variants in nHH/KS genes. ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.

Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis

BackgroundAcute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. ObjectivesThe aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis. MethodsFor this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ResultsOf 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children). ConclusionsGenetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.

A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance and cancer, thyroid, and other phenotypes in 2 population-scale cohorts

PurposePopulation-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well characterized in children with a pathogenic DICER1 (HGNC ID:17098) variant. Here, the prevalence, penetrance, and phenotype of pathogenic germline DICER1 variants in adults were investigated in 2 population-scale cohorts. MethodsVariant pathogenicity was classified using published DICER1 ClinGen criteria in the UK Biobank (469,787 exomes; unrelated: 437,663) and Geisinger (170,503 exomes; unrelated: 109,789) cohorts. In the UK Biobank cohort, cancer diagnoses in the EHR, cancer, and death registry were queried. For the Geisinger cohort, the Geisinger Cancer Registry and EHR were queried. ResultsIn the UK Biobank, there were 46 unique pathogenic DICER1 variants in 57 individuals (1:8242; 95% CI: 1:6362-1:10,677). In Geisinger, there were 16 unique pathogenic DICER1 variants (including 1 microdeletion) in 21 individuals (1:8119; 95% CI: 1:5310-1:12,412). Cohorts were well powered to find larger effect sizes for common cancers. Cancers were not significantly enriched in DICER1 heterozygotes; however, there was a ∼4-fold increased risk for thyroid disease in both cohorts. There were multiple ICD10 codes enriched >2-fold in both cohorts. ConclusionEstimates of pathogenic germline DICER1 prevalence, thyroid disease penetrance, and cancer phenotype from genomically ascertained adults are determined in 2 large cohorts.

Abstract 6133: Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study

Abstract Background: Individuals in Tijuana have been identified as having multicultural and racial diversity. In Baja, California, Mexico, the prevalence and composition of cancer-predisposing germline variants in gynecologic cancers in Tijuana patients have not been evaluated. Aim and Methods: We aimed to evaluate the prevalence of pathogenic variants (PV) using a panel of 84 cancer-predisposing genes in breast, endometrial, and ovarian cancer from the General Hospital of Tijuana during the period of October 2021-October 2023, who were contacted and invited to participate in the evaluation. Pre- and post-test genetic counseling was given, and a questionnaire on personal, gyneco-obstetric, demographic, and lifestyle variables was conducted. Peripheral blood samples were obtained from all patients, and Next-generation sequencing (NGS) was performed on the Illumina commercial platform (Illumina, SD, USA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG). Data was collected and descriptive statistics was applied to describe the characteristics of the population. Results: A total of 51 patients were included in our cohort; 98.0% (50/51) were females and 2% (1/51) were males. Among study participants (mean age ±standard deviation: 46.1 ± 10.9), 49% reported a personal history of cancer (25/51). Diagnosis of breast cancer was present in 80.3% of the patients (41/51), 9% (5/51) with ovarian cancer, and 3.9% (2/51) with endometrial cancer. Twenty-five percent of participants (13/51) harbor a PV or likely pathogenic (LP) variant distributed among four cancer-risk genes (BRCA1, BRCA2, ATM, and TP53). The distribution by gene in the patients with a PV was: BRCA1 in 61% (8/13), BRCA2 in 23% (3/13), TP53 in 8% (1/13), and ATM in 8% (1/13). Whereas 39.2% (20/51) had variants of uncertain clinical significance in genes with ambiguous or non-well-established risk association for cancer (BARD1, AXIN2, GPC3, NF2, CEBPA, MSH3, ALK, DIS3L2, CDC73, BAP1, RAD51D, NF1, MSH2, BLM, NBN, BRCA2, BARD1, RUNX1, RECQL4, EGFR, PALB2, CASR, and POLD1), and 35.2% (18/51) had negative results for both; PV and VUS. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of the gynecological cancer population in Tijuana, Mexico, consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary cancer and implement appropriate preventative programs. Disparities in access to testing have a significant impact on affected populations, due in part to underrepresentation in surveys of regional cancer etiology and in genomic variant databases. Citation Format: Jorge Alberto Guadarrama-Orozco, Paula Leal-Anaya, Eva Guerrero-Santillan. Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6133.

Estimating multiplicity of infection, allele frequencies, and prevalences accounting for incomplete data.

Molecular surveillance of infectious diseases allows the monitoring of pathogens beyond the granularity of traditional epidemiological approaches and is well-established for some of the most relevant infectious diseases such as malaria. The presence of genetically distinct pathogenic variants within an infection, referred to as multiplicity of infection (MOI) or complexity of infection (COI) is common in malaria and similar infectious diseases. It is an important metric that scales with transmission intensities, potentially affects the clinical pathogenesis, and a confounding factor when monitoring the frequency and prevalence of pathogenic variants. Several statistical methods exist to estimate MOI and the frequency distribution of pathogen variants. However, a common problem is the quality of the underlying molecular data. If molecular assays fail not randomly, it is likely to underestimate MOI and the prevalence of pathogen variants. A statistical model is introduced, which explicitly addresses data quality, by assuming a probability by which a pathogen variant remains undetected in a molecular assay. This is different from the assumption of missing at random, for which a molecular assay either performs perfectly or fails completely. The method is applicable to a single molecular marker and allows to estimate allele-frequency spectra, the distribution of MOI, and the probability of variants to remain undetected (incomplete information). Based on the statistical model, expressions for the prevalence of pathogen variants are derived and differences between frequency and prevalence are discussed. The usual desirable asymptotic properties of the maximum-likelihood estimator (MLE) are established by rewriting the model into an exponential family. The MLE has promising finite sample properties in terms of bias and variance. The covariance matrix of the estimator is close to the Cramér-Rao lower bound (inverse Fisher information). Importantly, the estimator's variance is larger than that of a similar method which disregards incomplete information, but its bias is smaller. Although the model introduced here has convenient properties, in terms of the mean squared error it does not outperform a simple standard method that neglects missing information. Thus, the new method is recommendable only for data sets in which the molecular assays produced poor-quality results. This will be particularly true if the model is extended to accommodate information from multiple molecular markers at the same time, and incomplete information at one or more markers leads to a strong depletion of sample size.

Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes

BackgroundDespite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations.MethodsHere, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples.ResultsIn this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%).ConclusionsOur findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.

Prevalence of Fabry disease in patients with chronic kidney disease: A systematic review and meta-analysis

Fabry disease (FD) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. It has a wide range of clinical manifestations, typically related to the specific underlying GLA variant. One of the main features of FD is kidney involvement; therefore, several studies have addressed the prevalence of FD in all types of patients with chronic kidney disease. We performed a systematic review and meta-analysis of screening studies in chronic kidney disease patients, including those on dialysis, had undergone a kidney transplantation, and those who did not receive kidney replacement therapy, and assessed the prevalence of pathogenic variants in these cohorts. Fifty-five studies were included, involving a total of 84,062 individuals. Of these, 251 cases were positive for FD; a third of the reported GLA variants were of a benign phenotype (37.8%), followed by classical phenotype (31.7%), late onset (15.5%), and of uncertain significance (14.7%). The overall prevalence among dialysis patients was 0.10% (CI95%, 0.06–0.15), 0.28% (CI95%, 0.06–0.15) among patients with kidney transplantation, and 0.17% (CI95%, 0.11–0.39) among those without kidney replacement therapy. Although the overall prevalence of FD is low in patients with kidney involvement, screening, especially in patients who have not yet undergone kidney replacement therapy, is important, in order to provide timely and effective treatment interventions, including disease modifying therapies. The prevalence of kidney involvement in females with Fabry Disease is lower but this should not lead to inadequate follow up. Further research is also needed on the impact of genetic variants of uncertain significance to elucidate their role in Fabry disease.

Analysis of the genetic contribution to thoracic aortic aneurysm or dissection in a prospective cohort of patients with familial and sporadic cases in East China

BackgroundThoracic aortic aneurysm or dissections (TAADs) represent a group of life-threatening diseases. Genetic aetiology can affect the age of onset, clinical phenotype, and timing of intervention. We conducted a prospective trial to determine the prevalence of pathogenic variants in TAAD patients and to elucidate the traits related to harbouring the pathogenic variants. One hundred and one unrelated TAAD patients underwent genetic sequencing and analysis for 23 TAAD-associated genes using a targeted PCR and next-generation sequencing-based panel.ResultsA total of 47 variants were identified in 52 TAAD patients (51.5%), including 5 pathogenic, 1 likely pathogenic and 41 variants of uncertain significance. The pathogenic or likely pathogenic (P/LP) variants in 4 disease-causing genes were carried by 1 patient with familial and 5 patients with sporadic TAAD (5.9%). In addition to harbouring one variant causing familial TAAD, the FBN1 gene harboured half of the P/LP variants causing sporadic TAAD. Individuals with an age of onset less than 50 years or normotension had a significantly increased genetic risk.ConclusionsTAAD patients with a younger age at diagnosis or normotension were more likely to carry a P/LP variant; thus, routine genetic testing will be beneficial to a better prognosis through genetically personalized care prior to acute rupture or dissection.

Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.

Prevalence of pathogenic variants in non-BRCA genes and their impact on clinical practice in Argentina.

e22534 Background: The use of NGS has made it easier and more cost-effective to analyze genes associated with hereditary cancer predisposition syndromes. Germline alterations in breast cancer (BC) have an estimated prevalence of 10.7% of Pathogenic Variant or Likely Pathogenic (P/LP), with up to 8.0% in BRCA1/2 and 2.7% in CHEK2, ATM and PALB2 genes; they increase the risk of cancer 2 to 5 times. To date, two studies of P/LP in genes non-BRCA1/2 have been conducted in Argentina with frequencies of 4.5 and 4.7% in patients with personal and/or family history of BC. Methods: We report the frequency of P/LP in non-BRCA1/2 genes in patients with hereditary cancer criteria referred to the Oncogenetics Program at Hospital Privado Universitario de Córdoba between 01/2016 and 12/2022. A retrospective analysis was conducted on patients with BC, ovarian cancer (OC), pancreatic cancer (PaC), or prostate cancer (PC) who had clinical criteria for hereditary cancer. NGS and/or Sanger methods were used to sequence the samples, and the frequency of P/LP, novel P, and their association with other variants were collected and associated with the clinical features of the index case. Results: Of 283 cases studied, 85 (30.0%) were P/LP, with 53 (18.7%) detected in BRCA1/2 and 32 (11.3%) in other genes. Among the 32 mutations found in non-BRCA1/2 genes, the frequency of P/LP was 4.59% for PALB2 and 2.47% for CHEK2, 1.06% for TP53, 0.7% for MUTHY and 0.35% each for ATM, BRIP1, FANCC, MLH1, MSH2, FANCM and PTEN. The cases studied correspond to BC (75%), PaC (9.3%) and asymptomatic patients (15.7%), two of which belonged to families with an identified mutation in PALB2, other two in CHEK2, and one with no available index case with a mutation in ATM. The age at diagnosis in the cases with personal history was 44.5 years (20-66) with a very early age in the cases with TP53 mutations and two cases with PALB2 variants. Of the total mutations in non-BRCA1/2 genes, two were found to be associated with other pathogenic mutations and 12 were associated with VUS. Within our study, four remarkable findings were identified in PALB2 gene: 1) five unrelated families share the pathogenic c.1653T > A; 2) two unrelated families share the pathogenic c.1959T > A; 3) the novel c.2872_2875del LP variant was detected and 4) the frequency of the variant c.1653T > A suggests the possibility of a founder effect. Our study shows a higher frequency of P/LP in non-BRCA genes than those reported in Argentina and Latin America, which may be due to the selection of a population with family and/or personal history of cancer. Conclusions: It is important to perform multi-gene testing including moderate-penetrance genes to determine the hereditary susceptibility to cancer in our population and to identify vulnerable groups that require more specialized surveillance than the general population. This will help individuals with a higher risk of developing cancer to take effective preventive actions.

Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy-associated genes: A subgroup analysis of the PARADIGM-HF trial.

To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj ] = 4 × 10-3 ), leaner (27.8 kg/m2 vs. 29.4 kg/m2 ; padj = 3.2 × 10-3 ), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10-3 ), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10-4 ). Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology.

Prevalence of Pathogenic Variants in Dilated Cardiomyopathy-Associated Genes in Patients Evaluated for Cardiac Sarcoidosis.

Prevalence of Pathogenic Variants in Dilated Cardiomyopathy-Associated Genes in Patients Evaluated for Cardiac Sarcoidosis.

High Prevalence of Collagenopathies in Preterm- and Term-Born Children With Periventricular Venous Hemorrhagic Infarction.

The aim of this study was to evaluate genetic risk factors in term-born children with antenatal periventricular hemorrhagic infarction (PVHI), presumed antenatal periventricular venous infarction and periventricular hemorrhagic infarction in preterm neonates. Genetic analysis and magnetic resonance imaging were performed in 85 children: term-born children (≥36 gestational weeks) with antenatal periventricular hemorrhagic infarction (n = 6) or presumed antenatal (n = 40) periventricular venous infarction and preterm children (<36 gestational weeks) with periventricular hemorrhagic infarction (n = 39). Genetic testing was performed using exome or large gene panel (n = 6700 genes) sequencing. Pathogenic variants associated with stroke were found in 11 of 85 (12.9%) children with periventricular hemorrhagic infarction/periventricular venous infarction. Among the pathogenic variants, COL4A1/A2 and COL5A1 variants were found in 7 of 11 (63%) children. Additionally, 2 children had pathogenic variants associated with coagulopathy, whereas 2 other children had other variants associated with stroke. Children with collagenopathies had significantly more often bilateral multifocal stroke with severe white matter loss and diffuse hyperintensities in the white matter, moderate to severe hydrocephalus, moderate to severe decrease in size of the ipsilesional basal ganglia and thalamus compared to children with periventricular hemorrhagic infarction/periventricular venous infarction without genetic changes in the studied genes (P ≤ .01). Severe motor deficit and epilepsy developed more often in children with collagenopathies compared to children without genetic variants (P = .0013, odds ratio [OR] = 233, 95% confidence interval [CI]: 2.8-531; and P = .025, OR = 7.3, 95% CI: 1.3-41, respectively). Children with periventricular hemorrhagic infarction/periventricular venous infarction have high prevalence of pathogenic variants in collagene genes (COL4A1/A2 and COL5A1). Genetic testing should be considered for all children with periventricular hemorrhagic infarction/periventricular venous infarction; COL4A1/A2 and COL5A1/A2 genes should be investigated first.

Frequency of Known Genetic Variants for Parkinson’s Disease in the PD GENEration Study Cohort (S42.002)

Frequency of Known Genetic Variants for Parkinson’s Disease in the PD GENEration Study Cohort (S42.002)

The association between age at breast cancer diagnosis and prevalence of pathogenic variants

PurposeYoung age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2.MethodsWe analyzed multi-gene panel testing results (09/2013–12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry.ResultsAn association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64–4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84–2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08–1.37) and CHEK2 (OR 1.34, 95% CI 1.21–1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98–1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13–2.56) and BRCA2 (OR 1.25, 95% CI 1.16–1.35).ConclusionsYoung age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.

Prevalence of pathogenic variants in cancer-predisposing genes in second cancer after childhood solid cancers.

Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors. We performed whole-exome sequencing in 14 pediatric patients with SMNs, including three brain tumors. Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer-predisposing genes (CPGs), which was significantly higher than in the control cohort (p < 0.01). The identified genes with variants were TP53 (n=2), DICER1 (n=1), PMS2 (n=1), and PTCH1 (n=1). In terms of the type of subsequent cancer, leukemia and multiple episodes of SMN had an exceptionally high rate of CPG pathogenic variants. None of the patients with germline variants had a family history of SMN development. Mutational signature analysis showed that platinum drugs contributed to the development of SMN in three cases, which suggests the role of platinum agents in SMN development. We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers.