A functional study for verifying the pathogenicity of a TRPM6 variant of uncertain significance: a novel non-canonical splicing-site variant in primary hypomagnesemia with secondary hypocalcemia

2021 ◽  
Author(s):  
Ping Wang ◽  
Ying Qian ◽  
Chunyu Gu ◽  
Xiufang Zhi ◽  
Linjie Pu ◽  
...  
Keyword(s):  
Functional Study ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Splicing Site

scholarly journals RNA Sequencing for Elucidating an Intronic Variant of Uncertain Significance (SDHD c.314+3A>T) in Splicing Site Consensus Sequences

2022 ◽  
Vol 42 (3) ◽  
pp. 376-379
Author(s):  
Hyunjung Gu ◽  
Jinyoung Hong ◽  
Woochang Lee ◽  
Sung-Bae Kim ◽  
Sail Chun ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Variant Of Uncertain Significance ◽  
Consensus Sequences ◽  
Uncertain Significance ◽  
Site Consensus ◽  
Splicing Site

scholarly journals Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up

2021 ◽  
Vol 7 (2) ◽  
pp. 22
Author(s):  
Jamie Matteson ◽  
Stanley Sciortino ◽  
Lisa Feuchtbaum ◽  
Tracey Bishop ◽  
Richard S. Olney ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Program Implementation ◽  
Screening Program ◽  
Birth Prevalence ◽  
Variant Of Uncertain Significance ◽  
Implementation Challenges ◽  
Screening Programs ◽  
Uncertain Significance ◽  
Long Term Follow Up

X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California’s experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.

scholarly journals First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Mario Tumminello ◽  
Antonella Gangemi ◽  
Federico Matina ◽  
Melania Guardino ◽  
Bianca Lea Giuffrè ◽  
...  
Keyword(s):  
Ectodermal Dysplasia ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Hypohidrotic Ectodermal Dysplasia ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Clinical Potential ◽  
Genomic Variant ◽  
Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

scholarly journals Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis

2022 ◽  
Vol 8 (1) ◽  
pp. e654
Author(s):  
Melissa Nel ◽  
Amokelani C. Mahungu ◽  
Nomakhosazana Monnakgotla ◽  
Gerrit R. Botha ◽  
Nicola J. Mulder ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Population Group ◽  
Genetic Ancestry ◽  
Familial Case ◽  
Data Sets ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Sporadic Als ◽  
Uncertain Significance ◽  
Lateral Sclerosis

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

scholarly journals Novel Mutations and Genes That Impact on Growth in Short Stature of Undefined Aetiology: The EPIGROW Study

2020 ◽  
Vol 4 (10) ◽  
Author(s):  
Reena Perchard ◽  
Philip George Murray ◽  
Antony Payton ◽  
Georgina Lee Highton ◽  
Andrew Whatmore ◽  
...  
Keyword(s):  
Short Stature ◽  
Sequence Data ◽  
Diagnostic Yield ◽  
Growth Disorders ◽  
Supporting Evidence ◽  
Missense Mutations ◽  
Nucleotide Polymorphisms ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
The Difference

Abstract Background Children with short stature of undefined aetiology (SS-UA) may have undiagnosed genetic conditions. Purpose To identify mutations causing short stature (SS) and genes related to SS, using candidate gene sequence data from the European EPIGROW study. Methods First, we selected exonic single nucleotide polymorphisms (SNPs), in cases and not controls, with minor allele frequency (MAF) < 2%, whose carriage fitted the mode of inheritance. Known mutations were identified using Ensembl and gene-specific databases. Variants were classified as pathogenic, likely pathogenic, or variant of uncertain significance using criteria from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. If predicted by ≥ 5/10 algorithms (eg, Polyphen2) to be deleterious, this was considered supporting evidence of pathogenicity. Second, gene-based burden testing determined the difference in SNP frequencies between cases and controls across all and then rare SNPs. For genotype/phenotype relationships, we used PLINK, based on haplotype, MAF > 2%, genotype present in > 75%, and Hardy Weinberg equilibrium P > 10–4. Results First, a diagnostic yield of 10% (27/263) was generated by 2 pathogenic (nonsense in ACAN) and a further 25 likely pathogenic mutations, including previously known missense mutations in FANCB, IGFIR, MMP13, NPR2, OBSL1, and PTPN11. Second, genes related to SS: all methods identified PEX2. Another 7 genes (BUB1B, FANCM, CUL7, FANCA, PTCH1, TEAD3, BCAS3) were identified by both gene-based approaches and 6 (A2M, EFEMP1, PRKCH, SOS2, RNF135, ZBTB38) were identified by gene-based testing for all SNPs and PLINK. Conclusions Such panels improve diagnosis in SS-UA, extending known disease phenotypes. Fourteen genes related to SS included some known to cause growth disorders as well as novel targets.

Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population

2020 ◽  
Vol 51 (1) ◽  
pp. 60-69 ◽  
Author(s):  
Azusa Yamamoto ◽  
Tatsuro Yamaguchi ◽  
Okihide Suzuki ◽  
Tetsuya Ito ◽  
Noriyasu Chika ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Molecular Characteristics ◽  
Variant Of Uncertain Significance ◽  
Dna Mismatch ◽  
Germline Variant ◽  
Uncertain Significance ◽  
Repair Genes

Abstract Background The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. Methods Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. Results Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). Conclusions This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

scholarly journals Next-Generation Sequencing in Order to Better Characterize a BRCA Variant of Uncertain Significance

2017 ◽  
Vol 10 (2) ◽  
pp. 634-637 ◽  
Author(s):  
Steven Sorscher ◽  
Shakti Ramkissoon
Keyword(s):  
Next Generation Sequencing ◽  
Germline Mutations ◽  
Allelic Frequency ◽  
Breast Cancers ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Predisposing Factor ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Generation Sequencing

BRCA germline mutations are the most common predisposing factor in familial breast-ovarian cancer syndrome families. However, many screened patients are identified as harboring BRCA variants of uncertain significance (VUS), rather than carrying deleterious germline mutations [Calo et al.: Cancers 2010; 2:1644–1660]. While such VUSs are typically reclassified as benign polymorphisms, this may occur years after the VUS is first identified [Murray et al.: Genet Med 2011; 13; 998–1005]. Loss of heterozygosity (LOH) of BRCA is nearly always the gatekeeper event in inherited BRCA-related breast cancer and LOH of BRCA is rare in sporadic cancers [Osorio et al.: Int J Cancer 2002; 99:305–309]. Here, we describe a patient identified as carrying a germline BRCA VUS. Tumor next-generation sequencing (NGS) demonstrated a very high mutation allelic frequency for that BRCA VUS, consistent with LOH. This case illustrates that since BRCA LOH is the typical mechanism of transformation in inherited BRCA-related breast cancers, NGS might be used to suggest that the BRCA VUS is actually cancer predisposing in a particular family. As a result, this may help patients make more informed decisions regarding screening and prophylactic therapy, long before official reclassification of the VUS occurs.

The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1510-1510
Author(s):  
Kara Noelle Maxwell ◽  
Daniel De Sloover ◽  
Lyndsey Emery ◽  
Bradley Wubbenhorst ◽  
Kurt P D'Andrea ◽  
...  
Keyword(s):  
Ovarian Tumor ◽  
Tp53 Mutation ◽  
Single Gene ◽  
Breast Tumors ◽  
Ovarian Tumors ◽  
Deleterious Mutations ◽  
Brca1 And Brca2 ◽  
Tp53 Mutations ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance

1510 Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.

Knowledge outcomes in a randomized trial of telephone vs. in-person disclosure of genetic testing: The COGENT study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1534-1534
Author(s):  
Nina Beri ◽  
Linda J. Patrick-Miller ◽  
Brian L. Egleston ◽  
Olufunmilayo I. Olopade ◽  
Michael J. Hall ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Randomized Trial ◽  
Genetic Knowledge ◽  
True Negative ◽  
Variant Of Uncertain Significance ◽  
Knowledge Change ◽  
Negative Results ◽  
Genetic Test Results ◽  
Uncertain Significance ◽  
Multivariable Analyses

1534 Background: Telephone disclosure (TD) of genetic testing is non-inferior to in-person disclosure (IPD) for most outcomes but did not meet non-inferiority for knowledge change. We sought to understand which concepts patients don’t understand and factors associated with lower knowledge. Methods: Patients were recruited to a multi-center, randomized trial (NCT01736345) comparing TD to IPD of genetic test results. 819 patients were randomized (IPD = 418; TD = 401); 165 declined randomization and requested IPD. Knowledge was assessed after pre-test counseling (V1) and test disclosure (V2). Results: There were no significant differences in genetic or multi-gene (MG) knowledge between disclosure groups after V1 and V2. On average, patients answered 73% (SD 1.19) of genetic knowledge and 57% (SD 1.78) of mg knowledge items correctly.After V1, most understood implications of a positive result (87%), that results are not deterministic (84%) and risks for their children (91%). Understanding of uninformative negative, true negative and variant of uncertain significance (VUS) results was lower (post-V1: 33%, 65%, 29%; post-V2 : 37%, 65%, 25%). In multivariable analyses, lower genetic knowledge after V1 was associated with study site, being older (p < 0.01), single (p < 0.01), non-white (p < 0.01), not Ashkenazi Jewish (p = 0.01), and not having a mutation in the family (p = 0.03), having more relatives with cancer (p < 0.01) and not graduating college (p < 0.01). Lower mg knowledge after V1 was associated with site and being non-white (p = 0.01). Lower genetic knowledge after V2 was not associated with disclosure method but associated with study site, being older (p < 0.01), not graduating college (p < 0.01) and being non-white (p < 0.01). Lower mg knowledge after V2 was only associated with not graduating college (p = 0.02). Conclusions: While there were no significant differences in genetic knowledge by disclosure method, understanding of several concepts (e.g. VUS and negative results) were lower regardless of arm. Several factors, including age, education and race/ethnicity were associated with lower knowledge. Interventions to improve genetic knowledge in real-world and diverse populations are needed. Clinical trial information: NCT07136345.

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