Diagnostic yield of advanced genetic testing in patients with hereditary neuropathies: A retrospective single‐site study

Felice, Kevin J.; Whitaker, Charles H.; Khorasani, Sadaf

doi:10.1002/mus.27368

Cited by 5 publications

(3 citation statements)

References 66 publications

(136 reference statements)

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“…Four of five patients had molecular diagnosis who underwent WES analysis. The diagnostic yield was compatible with literature 20,21 . The diagnostic rate in pediatric age group (54%) was higher than adult age group (39%).…”

Section: Gnb4 Litaf Mfn2supporting

confidence: 84%

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

Ceylan

Habiloğlu

Çavdarlı

et al. 2023

Rev. Assoc. Med. Bras.

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OBJECTIVE: Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. METHODS: This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. RESULTS: In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Wholeexome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. CONCLUSION: The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.

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Section: Gnb4 Litaf Mfn2supporting

confidence: 84%

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

Ceylan

Habiloğlu

Çavdarlı

et al. 2023

Rev. Assoc. Med. Bras.

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“…This approach has been transformed by the advent of NGS, where several disease-associated genes are tested in parallel. Nevertheless, the diagnostic rate of massive parallel sequencing tests described in the literature ranges from 4.6% to 93%, according to the analyzed cohort [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In routine clinical practice, the NGS approach more realistically allows us to reach a genetic diagnosis in 30% of genetically undetermined patients when PMP22 duplication has been previously ruled out [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years

Gemelli

Geroldi

Massucco

et al. 2022

Life

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Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.

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“…As the number of CMT genes corresponding to the different subtypes continues to expand, the likelihood of identifying a causative genetic variant is increasing. In a retrospective, single-center study, gene panel testing of 108 patients with CMT identified 17 patients (15.7%) with pathogenic or likely pathogenic variants [55]. In a nationwide laboratory study in Japan, the combination of microarray, gene panel sequencing, and WES of 2598 cases identified pathogenic or likely pathogenic variants in 798 patients (30.7%) [56].…”

Section: Neuromuscular Disordersmentioning

confidence: 99%

The Diagnostic Landscape of Adult Neurogenetic Disorders

Waung,

Ma,

Wheeler

et al. 2023

Biology

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Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

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Diagnostic yield of advanced genetic testing in patients with hereditary neuropathies: A retrospective single‐site study

Cited by 5 publications

References 66 publications

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years

The Diagnostic Landscape of Adult Neurogenetic Disorders

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