A clinical case of telomeropathy with heterozygous RTEL1 variant c.3791G>A (p.Arg1264His): discussion of bone marrow transplantation and multisystem management

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

Background: Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods :Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS),likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results: The three racial/ethnic groups have similar percentages of BRCA1 and BRCA2pathogenic variants. However, Caucasians have considerably more pathogenic variants in lesser penetrant genes [see Table 1]. Conclusions: Racial/ethnic groups vary by volume of lesser penetrant genes with Caucasians having the highest numbers. Correlation by SNP heritage assignment may lead to a better understanding of these differences. Gene NameAshkenazi PV% Askenazi PVs% of PV subjects AshkenaziAshkenazi VUS%VUS Ashkenazi VUS% of subjects VUS AshkenaziAsian% Asian PVs% of PV subjects AsianAsian VUS%VUS Asian mutations% of subjects VUS AsianBlack/African% Black/African PVs% of PV subjectsBlack/AfricanBlack/African VUS%VUS Black/Africanmutations% of subjects VUSBlack/AfricanCaucasian% Caucasian PVs% of PV subjects CaucasianCaucasian VUS% Caucasian Mutations% of subjects VUS CaucasianHispanic% Hispanic PVs% of PV subjects HispanicHispanic VUS% Hispanic Mutations% of subjects VUS HispanicOther% Other PVs% of PV subjects OtherOther RE VUS% Other RE Mutations% of subjects VUS Other#PV Total% Total PV#VUS TotalBRCA20.00%0.00%0.00%0.00%125.00%25.00%24.17%4.26%531.25%31.25%34.62%4.76%3414.47%16.50%122.42%2.44%815.69%18.18%45.26%5.48%211.11%12.50%36.67%6.82%5014.97%24BRCA1327.27%30.00%0.00%0.00%0.00%0.00%36.25%6.38%318.75%18.75%23.08%3.17%177.23%8.25%91.81%1.83%1631.37%36.36%11.32%1.37%211.11%12.50%24.44%4.55%4112.28%17CHEK20.00%0.00%112.50%12.50%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%2711.49%13.11%51.01%1.02%11.96%2.27%0.00%0.00%15.56%6.25%12.22%2.27%298.68%8ATM19.09%10.00%0.00%0.00%0.00%0.00%510.42%10.64%0.00%0.00%812.31%12.70%218.94%10.19%346.85%6.92%35.88%6.82%911.84%12.33%0.00%0.00%36.67%6.82%257.49%59CHEK2/1100delC19.09%10.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%104.26%4.85%30.60%0.61%23.92%4.55%22.63%2.74%0.00%0.00%0.00%0.00%133.89%6MUTYH0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%114.68%5.34%51.01%1.02%11.96%2.27%22.63%2.74%15.56%6.25%12.22%2.27%133.89%8PALB20.00%0.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%72.98%3.40%71.41%1.43%35.88%6.82%11.32%1.37%15.56%6.25%12.22%2.27%113.29%10BLM19.09%10.00%0.00%0.00%0.00%0.00%48.33%8.51%0.00%0.00%34.62%4.76%93.83%4.37%112.22%2.24%0.00%0.00%22.63%2.74%0.00%0.00%0.00%0.00%102.99%20MITF0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%83.40%3.88%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%0NBN0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%11.54%1.59%83.40%3.88%40.81%0.81%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%5FH327.27%30.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%41.70%1.94%40.81%0.81%0.00%0.00%11.32%1.37%0.00%0.00%0.00%0.00%72.10%5MSH619.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%0.00%0.00%4.62%4.76%31.28%1.46%132.62%2.65%23.92%4.55%22.63%2.74%15.56%6.25%0.00%0.00%72.10%19MUTYH-Biallelic/Compound Heterozygous0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%52.13%2.43%10.20%0.20%11.96%2.27%0.00%0.00%15.56%6.25%0.00%0.00%72.10%1MUTYH-Monoallelic0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%16.25%6.25%0.00%0.00%52.13%2.43%0.00%0.00%11.96%2.27%0.00%0.00%0.00%0.00%0.00%0.00%72.10%0PMS219.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%16.25%6.25%11.54%1.59%52.13%2.43%51.01%1.02%0.00%0.00%33.95%4.11%0.00%0.00%0.00%0.00%72.10%10Other00.00%0.00%562.50%62.50%375.00%75.00%3164.58%65.96%531.25%31.25%4467.69%69.84%6125.96%29.61%38377.22%78.00%1325.49%29.55%4964.47%67.12%950.00%56.25%3475.56%77.27%9127.25%546Grand Total11PV Ash108VUS Ash84PV Asi448Asi VUS4716PV Bla1665VUS Bla63235PV Cau206496VUS Cau49151PV His4476VUS His7318PV Oth1645VUS Oth44334334 PV Mutations Found738 Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of common cancer genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-19.

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Using Molecular Diagnostics for Inherited Retinal Dystrophies: The 6 "I"s That Are Necessary to Diagnose 2 Eyes Genetically.

BackgroundLynch syndrome is a hereditary cancer syndrome associated with high risks of colorectal and endometrial cancer that is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Accurate classification of variants identified in these genes as pathogenic or benign enables informed medical management decisions. Previously, we developed a clinical History Weighting Algorithm (HWA) for the classification of variants of uncertain significance (VUSs) in BRCA1 and BRCA2. The BRCA1/2 HWA is based on the premise that pathogenic variants in these genes will be identified more often in individuals with strong personal and/or family histories of breast and/or ovarian cancer, while the identification of benign variants should be independent of cancer history. Here we report the development of a similar HWA to allow for classification of VUSs in genes associated with Lynch syndrome using data collected through both syndrome-specific and pan-cancer panel testing.MethodsUpon completion of algorithm development, the HWA was tested using simulated variants constructed from 79,214 probands, as well as 379 true variants. Positive (PPV) and negative predictive values (NPV) were calculated on a per gene basis.Results25,500 pathogenic and 50,500 benign simulated variants were analyzed using the HWA and the PPVs and NPVs for each gene were greater than 0.997 and 0.999, respectively. The HWA was also evaluated using 100 trials for each of the 379 true variants. PPVs of >0.998 and NPVs of >0.999 were obtained for all genes.ConclusionsWe have developed and implemented a HWA to aid in the classification of VUSs in genes associated with Lynch syndrome. The work presented here demonstrates that this HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with high accuracy.

Background and Aims Genetic testing in patients with autosomal dominant polycystic kidney disease (ADPKD) provides critical information about the disease, enhances prognostic evaluation, and plays a vital role in patient management. This study aims to investigate the genetic etiology of ADPKD in a cohort of Greek patients. Method A total of 135 ADPKD patients (62 females, 73 males; median age at diagnosis: 24 years, IQR: 17–34) were included in this study, with 27 patients diagnosed before the age of 15. Magnetic resonance imaging (MRI) was performed in 104 patients, revealing more than 10 renal cysts. Children with a positive family history (FH) displayed at least one cyst in echography, while two without FH had multiple renal cysts. All patients underwent genetic testing, including targeted next-generation sequencing (tNGS) of over 600 clinically relevant genes, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA). Results Genetic analysis confirmed a diagnosis in 126 of 135 patients (93.3%). Variants in the PKD1 gene were detected in 90 patients (66.6%), with 66 (75.9%) resulting in truncated protein production. Variants in the PKD2 gene were identified in 20 patients (14.8%). The variant types of PKD1 and PKD2 genes are illustrated in Fig. 1. Genetic variants in genes other than PKD1 and PKD2 were identified in 12 patients (8.9%), including GANAB (3 cases), IFT140 (2 cases), and SEC61B gene (2 cases, a father and son, with high hepatic cyst charge), the later classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. In two other cases involving a father 73 and a daughter 35 years old (who had 3 other family members with chronic renal failure of unknown etiology), two variants were identified in PKHD1 and COL4A3 genes, both classified as VUS. Finally, three cases with multiple kidney cysts showed variants in DNAJB11, SEC63, and SLC3A1 genes, which were classified as frameshift, splicing and missense, respectively. Simultaneous variants in PKD1 and other genes were observed in four patients. In three related patients (a father, son, and grandson with typical polycystic kidneys), variants in PKD1 and PKHD1 were identified, both classified as VUS. In another case (categorized as Mayo Imaging Class 1C), a pathogenic frameshift mutation in PKD1 and a pathogenic missense mutation in COL4A4 were detected. Overall, 42.9% of identified variants were classified as pathogenic, 50% as likely pathogenic, and 7.1% (9 cases) as VUS, according to ACMG guidelines. Conclusion This study highlights the genetic diversity of ADPKD in Greek patients. The predominance of the variants identified in PKD1 and PKD2 genes, particularly those leading to truncated Polycystin-1 production, underscores their critical role in ADPKD pathogenesis. The identification of variants in other genes such as GANAB, IFT14O etc. reveals the genetic heterogeneity of the disease. The findings also reveal the complexity of genetic counselling, as double mutations and VUS are frequently observed, in patients with typical and atypical phenotypes, emphasizing the importance of comprehensive genetic testing in the diagnosis and management of ADPKD.

Severe early childhood caries (S-ECC) is a multifactorial disease with strong evidence of genetic inheritance. Previous studies suggest that variants in taste genes are associated with dental caries due to the role of taste proteins in mediating taste preferences, oral innate immunity, and important host-microbial interactions. However, few taste genes have been investigated in caries studies. Therefore, the associations of genetic variants in sweet, bitter, umami, salt, sour, carbonation, and fat taste-related genes with S-ECC and plaque microbial composition (16S and ITS1 rRNA sequencing) were evaluated. The results showed that sixteen variants in seven taste genes (SCNN1D, CA6, TAS2R3, OTOP1, TAS2R5, TAS2R60, and TAS2R4) were associated with S-ECC. Twenty-one variants in twelve taste genes were correlated with relative abundances of bacteria or fungi. These results suggest that S-ECC risk and composition of the plaque microbiome can be partially influenced by genetic variants in genes related to taste sensation.

A novel variant in KCNQ1 associated with short QT syndrome

To investigate potential genetic variants associated with spontaneous posterior capsule rupture (sPCR) in patients diagnosed with dead bag syndrome (DBS). Iladevi Cataract and IOL Research Centre and Raghudeep Eye Hospital, Ahmedabad, Gujarat, India. Laboratory study. Blood samples were collected from 30 patients with DBS and 37 controls. Whole-exome sequencing was performed. Genetic variants in genes encoding extracellular matrix components of the lens capsule were screened. The association of selected variants with DBS was analyzed using the Optimal Unified Sequence Kernel Association Test in R and Logistic Regression. Genes showing significant associations were further analyzed using in silico predictions through the Ensembl Variant Effect Predictor to assess their potential impact on protein function. Three genes- FBN2 ( P = .027, odds ratio [OR] = 4.9, 95% CI = 0.56-42.72), LAMB1 ( P = .005, OR = 11.0, 95% CI = 1.56-77.31), and LAMB2 ( P = .091, OR = 8.2, 95% CI = 1.03-65.57)-were found to be positively associated with DBS. A total of 15 distinct, functionally deleterious genetic variants, including 6 in FBN2 , 3 in LAMB1 , and 6 in LAMB2 genes, were identified across 17 (56.7%) patients with DBS. Of the 17 patients, 5 (29.4%) carried a common genetic variant (p.Ile1547Thr; rs35915664, minor allele frequency = 0.016) in the LAMB1 gene, which was absent in controls. The genetic variants found in FBN2 , LAMB1 , and LAMB2 genes may compromise the strength and stability of the lens capsule over time, predisposing individuals to DBS and sPCR later in life. The study shows for the first time, to the authors' knowledge, that the DBS has a genetic predisposition.

Influence of Cytokine-Related genetic variants in TNF, IL6, IL1β, and IFNγ genes in the thalidomide treatment for Erythema nodosum leprosum in a Brazilian population sample.

Background: Surveillance is a fundamental tool in the early detection and secondary prevention of many cancers. For women at increased genetic risk of breast cancer, mammography and breast magnetic resonance imaging (MRI) serve as the standard screening modalities. Use of surveillance mammography and MRI has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely pathogenic variants (P/LP). To address this gap, we examined the use of breast cancer surveillance and breast surgery in women who underwent multiple gene sequencing in a multicenter cohort of patients. We also expanded the surveillance literature by assessing correlates of breast MRI and mammography among women with VUS and investigating how rates of imaging changed over time after genetic testing. Methods: Using data from two cancer settings, we calculated use of risk reducing mastectomy (RRM) and surveillance for all women at genetically elevated risk of breast cancer, regardless of their personal history of breast cancer, with VUS or P/LP variants in a breast cancer susceptibility gene of high penetrance (BRCA1, BRCA2, PALB2, PTEN, TP53) and moderate penetrance (ATM, CDH1, CHEK2, NBN, NF1, STK11). The primary outcome was longitudinal use of surveillance mammography and breast MRI for women during the 13-month span after genetic testing, and each subsequent 13-month period up to 6 years afterwards. Results: Of 889 women, those with and without personal history of breast cancer were similar with regards to race/ethnicity, marital status, and high- or average-risk status. However, women with a personal history of breast cancer were on average older (54.1 vs 48.2 years), had longer follow-up time since genetic testing (3.4 vs 3.0 years), and were more likely to have VUS (62.5% vs 37.7%) compared to those without personal history of breast cancer. VUS carriers were less likely to undergo RRM compared to those with P/LP (HR=0.17, p=< 0.001) and high-risk women were more likely to undergo RRM than average-risk women (HR=3.91, p=0.005). Longitudinally, surveillance use among unaffected women decreased from 49.8% in the first year to 31.2% in the sixth year after genetic testing. In comparison, a greater proportion of women with a personal history of breast cancer underwent surveillance, which increased from 59.3% in the first year to 63.6% in the sixth year after genetic testing. Mammography rates did not differ between women with P/LP and VUS within the first 13 months after genetic testing and up to 4 years afterwards. Over the first four years after genetic testing, women with VUS were less likely to undergo annual MRIs compared to P/LP. This observation was true for women without a personal history of breast cancer (OR=0.34, p=0.003; OR=0.37, p=0.03; OR=0.19, p=0.004 for years 1, 2, and 3 respectively) as well as for women with a personal history of breast cancer (OR=0.31, p<=0.001; OR=0.33, p=0.002; OR=0.37, p=0.012; OR=0.3, p=0.14 for years 1, 2, 3, and 4 respectively). Conclusion: In this study of surveillance mammography and breast MRI use among women at elevated risk of breast cancer, we found that women with P/LP variants in breast cancer susceptibility genes are more likely to undergo annual breast MRI compared to those with VUS, whereas there was no difference between the groups in their use of annual surveillance mammography. This study is one of the first to examine maintenance of breast surveillance in a sample of women at elevated risk of breast cancer with non-negative genetic test results in BRCA1/2 as well as non-BRCA1/2 genes, while adjusting for personal and family history of cancer. In addition, we found that VUS, whether in high or moderate penetrance breast cancer susceptibility genes, was associated with lower use of annual breast MRI compared to P/LP variants, and equivalent use of annual mammography. These results add important evidence to dispel the myth of VUS-associated mismanagement of care. Citation Format: Sukh Makhnoon, Minxing Chen, Brooke Levin, Megan Ensinger, Kristin Mattie, Generosa Grana, Sanjay Shete, Banu K. Arun, Susan K. Peterson. Use of breast surveillance between women with pathogenic variants and variants of uncertain significance in breast cancer susceptibility genes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-04.

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study were selected for independent replication in 5205 hypertensive patients and 5320 population-based controls, and successively in a cohort of 16537 individuals. A common variant (rs10860812) in the DRAM (damage-regulated autophagy modulator) locus showed association with hypertension (P = 0.008) in the replication study. The minor allele (A) had a protective effect (OR = 0.93; 95% CI 0.88–0.98 per A-allele), which replicates the association in the WTCCC GWA study. However, a second follow-up, in the larger cohort, failed to reveal an association with blood pressure. We further tested the endothelial-specific genes for co-localization with a panel of newly discovered SNPs from large meta-GWAS on hypertension or blood pressure. There was no significant overlap between those genes and hypertension or blood pressure loci. The result does not support the hypothesis that genetic variation in genes expressed in endothelium plays an important role for hypertension development. Moreover, the discordant association of rs10860812 with blood pressure in the case control study versus the larger Malmö Preventive Project–study highlights the importance of rigorous replication in multiple large independent studies.

Genetic Variation in Genes That Regulate T-Cell Differentiation and Function Is Associated with An Increased Risk of Developing B-Cell Non- Hodgkin Lymphoma

Prolidase deficiency (PD) is a rare inborn error of immunity due to autosomal recessive pathogenic variants in the PEPD gene. Clinical presentation of this condition is highly variable, making diagnosis difficult. The most common presentations of PD are cutaneous (ulcers) followed by dysmorphism, developmental delay, and frequent infections. Genetic testing can be helpful in the diagnosis of PD and other inborn errors of immunity. The limitations of genetic testing lie in the interpretation of genomic results for rare or ultra-rare disorders, particularly variants of unknown significance (VUS). Clinical correlation is still vital in the era of genomic medicine. We present a case of a two-year-old female who presented with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). HLH episodes were triggered by multiple organisms, including EBV. HLH was managed with systemic steroids and anakinra while stem cell transplant workup was being performed. While on therapy, type 1 and 2 IFN signaling were normal, but CXCL9 and IL-18 were elevated. Genetic testing identified a pathogenic variant in PEPD (deletion in exon 7) and a VUS c.79C>T p.(Arg27Trp). Other VUSs were found in NFAT5, POLD2, and POLE. HLH is reported in at least one patient with PD, making the diagnosis a consideration. Familial genetic study confirmed the pathogenic mutation was paternally inherited and VUS maternally inherited. The proband’s sister carried only the paternal pathogenic mutation. Urine amino acid studies showed marked proline elevation in the proband (similar to another known affected individual) and was normal in all other family members. Confirmation of two PEPD variants in trans, markedly elevated urine proline, and a phenotype compatible with PD allowed for reclassification of the VUS to likely pathogenic variant. The patient underwent matched HSCT from her sister. The patient so far has not had recurrence of her HLH. This case is the second known case of PD treated with HSCT. The first case resulted in fatality within the first 100 days of transplant due to invasive fungal infection. It is unclear if HSCT will correct the entirety of PD complications, but we are hopeful early intervention will reduce sequalae and improve quality of life.