Role of the CDKN2A Locus in Patients With Multiple Primary Melanomas

2005 ◽  
Vol 23 (13) ◽  
pp. 3043-3051 ◽  
Author(s):  
Susana Puig ◽  
Josep Malvehy ◽  
Cèlia Badenas ◽  
Anna Ruiz ◽  
Dolores Jimenez ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Case Series ◽  
Primary Melanoma ◽  
Phenotypic Characterization ◽  
Exon 2 ◽  
Variant Of Uncertain Significance ◽  
Multiple Primary ◽  
Uncertain Significance ◽  
Risk Patients ◽  
Total Body

Purpose We have studied a consecutive case series of patients with multiple primary melanoma (MPM) for the involvement of the melanoma susceptibility loci CDKN2A and CDK4. Patients and Methods One hundred four MPM patients (81 patients with two primary melanomas, 14 with three, five with four, one with five, two with six, and one with seven) were included. Results Seven different CDKN2A germline mutations were identified in 17 patients (16.3%). In total, we identified 15 CDKN2A exon 2, one exon 1α missense mutation, and one exon 1β frameshift mutation. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were more frequent in patients with familial history of melanoma (35.5%) compared with patients without (8.2%), with a relative risk (RR) of 4.32 (95% CI, 1.76 to 10.64; P = .001), and in patients with more than two melanomas (39.1%) compared with patients with only two melanomas (10%) with an RR of 3.29 (95% CI, 1.7 to 6.3; P = .002). The A148T polymorphism was more frequent in patients with MPMs than in the control population (P = .05). A variant of uncertain significance, A127S, was also detected in one patient. No CDK4 mutations were identified, suggesting that it has a low impact in susceptibility to MPM. Conclusion MPM patients are good candidates for CDKN2A mutational screening. These patients and some of their siblings should be included in a program of specific follow-up with total body photography and digital dermoscopy, which will result in the early detection of melanoma in this subset of high-risk patients and improve phenotypic characterization.

scholarly journals Whole Exome Sequencing and Molecular Modeling of a Missense Variant in TNFAIP3 That Segregates with Disease in a Family with Chronic Urticaria and Angioedema

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Antoneicka L. Harris ◽  
Patrick R. Blackburn ◽  
John E. Richter ◽  
Jennifer M. Gass ◽  
Thomas R. Caulfield ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chronic Urticaria ◽  
Periodic Fever ◽  
Missense Variant ◽  
Exon 2 ◽  
Variant Of Uncertain Significance ◽  
Whole Exome ◽  
Uncertain Significance ◽  
The Individual

Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual’s 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G>A (p.R22Q), in all affected members. Variants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease.

scholarly journals Value of systematic genetic screening of patients with amyotrophic lateral sclerosis

2021 ◽  
pp. jnnp-2020-325014
Author(s):  
Stephanie R Shepheard ◽  
Matthew D Parker ◽  
Johnathan Cooper-Knock ◽  
Nick S Verber ◽  
Lee Tuddenham ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Age Of Onset ◽  
Clinical Care ◽  
Case Series ◽  
Pathogenic Mutation ◽  
Gene Panel ◽  
Targeted Sequencing ◽  
Genetic Sequencing ◽  
Variant Of Uncertain Significance ◽  
Lateral Sclerosis

ObjectiveThe clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.MethodsWe performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.Results21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).ConclusionsRoutine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.

scholarly journals Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Claudia L. Gaefke ◽  
Jonathan Metts ◽  
Donya Imanirad ◽  
Daime Nieves ◽  
Paola Terranova ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Clinical Manifestations ◽  
Case Series ◽  
Missense Variant ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Generational Cohort ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Exon 9 ◽  
Lymphoproliferative Syndrome

Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in FAS (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.

scholarly journals Gaps in Receipt of Clinically Indicated Genetic Counseling After Diagnosis of Breast Cancer

2018 ◽  
Vol 36 (12) ◽  
pp. 1218-1224 ◽  
Author(s):  
Steven J. Katz ◽  
Kevin C. Ward ◽  
Ann S. Hamilton ◽  
M. Chandler Mcleod ◽  
Lauren P. Wallner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Counseling ◽  
Los Angeles ◽  
Early Stage ◽  
Pathogenic Mutation ◽  
Variant Of Uncertain Significance ◽  
Younger Women ◽  
Genetic Test Results ◽  
Uncertain Significance ◽  
Risk Patients

Purpose Little is known about the extent to which genetic counseling is integrated into community practices for patients newly diagnosed with breast cancer. We examined the receipt of clinically indicated genetic counseling in these patients. Patients and Methods We surveyed 5,080 patients between the ages of 20 and 79 years, diagnosed from July 2013 to August 2015 with early-stage breast cancer and reported to the SEER registries of Georgia and Los Angeles County. Surveys were linked to SEER clinical data and genetic test results. The study sample (N = 1,711) comprised patients with indications for formal genetic risk evaluation. Results Overall, 47.4% did not get tested, 40.7% tested negative, 7.4% had a variant of uncertain significance only, and 4.5% had a pathogenic mutation. Three quarters (74.6%) received some form of genetic counseling (43.5%, formal counseling and 31.1%, physician-directed discussion). Virtually all tested patients (96.1%) reported some form of genetic discussion (62.2%, formal counseling and 33.9%, physician-directed discussion). However, only one half (50.6%) of those not tested received any discussion about genetics. Younger women were more likely to report some type of counseling, controlling for other factors: odds ratio, 4.5 (95% CI, 2.6 to 8.0); 1.9 (95% CI, 1.1 to 3.3); and 1.5 (95% CI, 1.0 to 2.3) for women younger than 50 years of age, 50 to 59 years of age, and 60 to 69 years of age versus those 70 years of age and older. Patients’ assessments of the amount of information they received about whether to get tested were similarly high whether they were counseled by a genetics expert or by a physician only (80.8% v 79.4% stated information was just right, P = .59). Conclusion Less than one half (43.5%) of patients with clinical indications received formal genetic counseling. There is a large gap between mandates for timely pretest formal genetic counseling in higher-risk patients and the reality of practice today.

Assessment of germ-line and somatic alterations in main candidate genes among patients with multiple primary melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8581-8581
Author(s):  
Giuseppe Palmieri ◽  
MariaCristina Sini ◽  
Vincenzo De Giorgi ◽  
Amelia Lissia ◽  
Daniela Massi ◽  
...  
Keyword(s):  
Germ Line ◽  
Age Of Onset ◽  
Primary Melanoma ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
Braf Mutations ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Multiple Primary ◽  
Somatic Alterations

8581 Background: We have studied a series of patients with multiple primary melanoma (MPM) for the involvement of the key-regulator genes in susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease. Methods: Genomic DNA from peripheral blood of 63 MPM patients (54 cases with two primary melanomas, 8 with three, and 1 with four) were screened for germline mutations in p16CDKN2A and p14CDKN2A genes by automated DNA sequencing. Melanoma families were identified according to standardized criteria: 9 (14%) patients were classified as familial cases. Paired synchronous and/or asynchronous MPM tissues (N=100) from same patients (N=46) were analyzed for somatic mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes. Results: Overall, 6 (10%) different CDKN2A germline mutations were identified: 5 in p16CDKN2A and 1 in p14CDKN2A. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were significantly more frequent in patients with familial history of melanoma (5/9; 56%) compared with patients without (1/54; 2%) (P<0.001), and in patients with more than two melanomas (3/9; 33%) compared with patients with only two melanomas (3/54; 6%) (P=0.012). The debated A148T polymorphism was found at low level (2/54; 4%) in our series. Regarding genetic alterations at somatic level, BRAF mutations were identified in 36/100 (36%) primary melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was observed in 2/88 (2%) and 10/88 (11%) analyzed tissue samples, respectively. Considering all types of genetic events, paired samples presented a poorly consistent distribution of somatic alterations in same patients (52% consistency). Conclusions: Coexistence of MPM and familial recurrence of melanoma as well as the presence of more than two melanomas seem to be strong indications to address patients to CDKN2A mutational screening. The low consistency in genetic patterns of primary tumors from the same patients provide additional evidence that pathogenetic mechanisms of melanomagenesis are heterogeneous and molecularly different cell types may be generated in multiple primary melanoma.

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 Novel MSX1 variants identified in families with nonsyndromic oligodontia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jinglei Zheng ◽  
Miao Yu ◽  
Haochen Liu ◽  
Tao Cai ◽  
Hailan Feng ◽  
...  
Keyword(s):  
Current Data ◽  
Phenotypic Characterization ◽  
Functional Evaluation ◽  
Gene Variants ◽  
Chinese Families ◽  
Whole Exome ◽  
Bioinformatics Databases ◽  
Uncertain Significance ◽  
Vitro Analysis

AbstractThe goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia, and a series of bioinformatics databases were used for variant confirmation and functional prediction. Phenotypic characterization of the members of these families was described, and an in vitro analysis was performed for functional evaluation. Five novel MSX1 heterozygous variants were identified: three missense variants [c.662A>C (p.Q221P), c.670C>T (p.R224C), and c.809C>T (p.S270L)], one nonsense variant [c.364G>T (p.G122*)], and one frameshift variant [c.277delG (p.A93Rfs*67)]. Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P, p.R224C, p.G122*, and p.A93Rfs*67 variants compared to the wild type. Three variants (p.Q221P, p.G122*, and p.A93Rfs*67) were classified as pathogenic or likely pathogenic, while p.S270L and p.R224C were of uncertain significance in the current data. Moreover, we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss. Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.

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 Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series

Neurogenetics ◽  
2021 ◽  
Author(s):  
Luca Magistrelli ◽  
Roberta Croce ◽  
Fabiola De Marchi ◽  
Chiara Basagni ◽  
Miryam Carecchio ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Case Series ◽  
Dominant Trait ◽  
Autosomal Dominant Trait ◽  
Phenotypic Spectrum ◽  
Primary Familial Brain Calcification ◽  
Psychiatric Disturbances ◽  
Brain Calcification ◽  
Uncertain Significance ◽  
Six Genes

AbstractPrimary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.

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.

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