scholarly journals Cohort Analysis of 67 Charcot-Marie-Tooth Italian Patients: Identification of New Mutations and Broadening of Phenotype Expression Produced by Rare Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Rosangela Ferese ◽  
Rosa Campopiano ◽  
Simona Scala ◽  
Carmelo D’Alessio ◽  
Marianna Storto ◽  
...  
Keyword(s):  
Rare Variants ◽  
Cohort Analysis ◽  
Sensory Neuropathy ◽  
Medical Genetics ◽  
Protein Domain ◽  
Tail Domain ◽  
Clinical Trial Registration ◽  
Charcot Marie Tooth ◽  
Uncertain Significance ◽  
Phenotype Expression

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited motor sensory neuropathy, which clusters a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with different phenotypes. The goal of this study is to identify the genetic features in the recruited cohort of patients, highlighting the role of rare variants in the genotype-phenotype correlation. We enrolled 67 patients and applied a diagnostic protocol including multiple ligation-dependent probe amplification for copy number variation (CNV) detection of PMP22 locus, and next-generation sequencing (NGS) for sequencing of 47 genes known to be associated with CMT and routinely screened in medical genetics. This approach allowed the identification of 26 patients carrying a whole gene CNV of PMP22. In the remaining 41 patients, NGS identified the causative variants in eight patients in the genes HSPB1, MFN2, KIF1A, GDAP1, MTMR2, SH3TC2, KIF5A, and MPZ (five new vs. three previously reported variants; three sporadic vs. five familial variants). Familial segregation analysis allowed to correctly interpret two variants, initially reported as “variants of uncertain significance” but re-classified as pathological. In this cohort is reported a patient carrying a novel familial mutation in the tail domain of KIF5A [a protein domain previously associated with familial amyotrophic lateral sclerosis (ALS)], and a CMT patient carrying a HSPB1 mutation, previously reported in ALS. These data indicate that combined tools for gene association in medical genetics allow dissecting unexpected phenotypes associated with previously known or unknown genotypes, thus broadening the phenotype expression produced by either pathogenic or undefined variants.Clinical trial registration: ClinicalTrials.gov (NCT03084224).

scholarly journals The Probability of Pathogenicity in Clinical Genetic Testing: A Solution for the Variant of Uncertain Significance

2016 ◽  
Vol 5 (4) ◽  
pp. 52
Author(s):  
Michael Gollob ◽  
Jeffrey S. Rosenthal ◽  
Kevin Thorpe
Keyword(s):  
Genetic Testing ◽  
Genetic Variant ◽  
Rare Variants ◽  
Direct Calculation ◽  
Medical Genetics ◽  
Clinical Genetic ◽  
Rare Genetic Variant ◽  
Variant Of Uncertain Significance ◽  
Clinical Genetic Testing ◽  
Uncertain Significance

We present a direct calculation for determining the probability that a rare genetic variant is the cause of an observed disease, under appropriate assumptions, in terms of the joint prevalence of the disease and of rare variants.  Our calculation provides a resolution of the so-called ``variant of unknown (or uncertain) significance'' problem, which has plagued medical genetics researchers.

scholarly journals Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples

2017 ◽  
Vol 13 (4) ◽  
pp. e1005428 ◽  
Author(s):  
Thomas A. Peterson ◽  
Iris Ivy M. Gauran ◽  
Junyong Park ◽  
DoHwan Park ◽  
Maricel G. Kann
Keyword(s):  
Rare Variants ◽  
Protein Domain

scholarly journals Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes

2020 ◽  
Vol 57 (9) ◽  
pp. 624-633 ◽  
Author(s):  
Martin Krenn ◽  
Matias Wagner ◽  
Christoph Hotzy ◽  
Elisabeth Graf ◽  
Sandrina Weber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
Focal Epilepsy ◽  
Diagnostic Yield ◽  
Mammalian Target Of Rapamycin ◽  
High Rate ◽  
Molecular Heterogeneity ◽  
Pathogenic Variants ◽  
Uncertain Significance

BackgroundThe genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE.Methods112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE.ResultsES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants.ConclusionThis study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years.

A Consensus Statement on the Surgical Treatment of Charcot-Marie-Tooth Disease

2020 ◽  
Vol 41 (7) ◽  
pp. 870-880 ◽  
Author(s):  
Glenn B. Pfeffer ◽  
Tyler Gonzalez ◽  
James Brodsky ◽  
John Campbell ◽  
Chris Coetzee ◽  
...  
Keyword(s):  
Consensus Statement ◽  
Sensory Neuropathy ◽  
Comprehensive Approach ◽  
Foot And Ankle ◽  
Clinical Experiences ◽  
Consensus Guidelines ◽  
Level Of Evidence ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Background: Charcot-Marie-Tooth (CMT) disease is a hereditary motor-sensory neuropathy that is often associated with a cavovarus foot deformity. Limited evidence exists for the orthopedic management of these patients. Our goal was to develop consensus guidelines based upon the clinical experiences and practices of an expert group of foot and ankle surgeons. Methods: Thirteen experienced, board-certified orthopedic foot and ankle surgeons and a neurologist specializing in CMT disease convened at a 1-day meeting. The group discussed clinical and surgical considerations based upon existing literature and individual experience. After extensive debate, conclusion statements were deemed “consensus” if 85% of the group were in agreement and “unanimous” if 100% were in support. Conclusions: The group defined consensus terminology, agreed upon standardized templates for history and physical examination, and recommended a comprehensive approach to surgery. Early in the course of the disease, an orthopedic foot and ankle surgeon should be part of the care team. This consensus statement by a team of experienced orthopedic foot and ankle surgeons provides a comprehensive approach to the management of CMT cavovarus deformity. Level of Evidence: Level V, expert opinion.

Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a

1993 ◽  
Vol 39 (9) ◽  
pp. 1845-1849 ◽  
Author(s):  
G W Hensels ◽  
E A Janssen ◽  
J E Hoogendijk ◽  
L J Valentijn ◽  
F Baas ◽  
...  
Keyword(s):  
Preliminary Investigation ◽  
Sensory Neuropathy ◽  
Disease Type ◽  
Chromosome 17 ◽  
Hereditary Neuropathy ◽  
Chromosomal Dna ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Abstract Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.

scholarly journals Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hannah Gelman ◽  
◽  
Jennifer N. Dines ◽  
Jonathan Berg ◽  
Alice H. Berger ◽  
...  
Keyword(s):  
Functional Data ◽  
Clinical Utility ◽  
Medical Genetics ◽  
Variant Interpretation ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Genetics And Genomics ◽  
New Guidelines

AbstractVariants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby increasing the clinical utility of genomic testing. Existing standards from the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) and new guidelines from the Clinical Genome Resource (ClinGen) establish the role of functional data in variant interpretation, but do not address the specific challenges or advantages of using functional data derived from multiplexed assays. Here, we build on these existing guidelines to provide recommendations to experimentalists for the production and reporting of multiplexed functional data and to clinicians for the evaluation and use of such data. By following these recommendations, experimentalists can produce transparent, complete, and well-validated datasets that are primed for clinical uptake. Our recommendations to clinicians and diagnostic labs on how to evaluate the quality of multiplexed functional datasets, and how different datasets could be incorporated into the ACMG/AMP variant-interpretation framework, will hopefully clarify whether and how such data should be used. The recommendations that we provide are designed to enhance the quality and utility of multiplexed functional data, and to promote their judicious use.

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