Coincidence of two genetic forms of Charcot–Marie–Tooth disease in a single family

Verny, Christophe; Ravisé, N; Leutenegger, Anne-Louise; F, Pouplard; Dubourg, Odile; Tardieu, S; Dubas, Frédéric; Brice, Alexis; Génin, Emmanuelle; LeGuern, Eric

doi:10.1212/01.wnl.0000142082.65144.ee

Cited by 27 publications

(23 citation statements)

References 9 publications

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“…Two represented phenotypic expansions of CMT2 caused by mutations in MFN2 (Figure 1A), where the clinical presentation made screening for MFN2 unlikely. One family showed two separate segregating causes of CMT [Verny et al, 2004], one X-linked and the other caused by compound heterozygous mutations in MED25 . A novel, likely disease causing allele was found in trans with the only known disease causing allele in this gene [Leal et al, 2001; Leal et al, 2009].…”

Section: Resultsmentioning

confidence: 99%

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

et al. 2015

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Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

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Section: Resultsmentioning

confidence: 99%

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

et al. 2015

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“…35,36 There is also a report of mutations in two genes related to Charcot–Marie–Tooth disease segregating in the same family as either a recessive trait or a sporadic trait, the latter of which was attributed to a de novo copy-number variant. 37 Given this locus heterogeneity, with evidence of a mutational load that has clinical consequences, as well as the ease of use and accuracy of the whole-genome sequencing methods we applied, clinical and genetics experts struggling to explain poorly understood high-penetrance genetic diseases can now seriously consider this approach for illuminating the molecular causes of these diseases. The approach may ultimately contribute to the care of patients and families living with such diseases.…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

Reid²,

et al. 2010

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BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. METHODS We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.

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“…Muscle atrophy and weakness progressively proceed toward proximal muscles, resulting first in a clumsy and waddling gait, and then in the need for a wheelchair from late childhood into adolescence. Facial, bulbar and diaphragmatic involvement have been reported in a few cases ( Refs 7,8,9). Houlden used molecular analysis to confirm the original case described by Tyson (Ref.…”

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confidence: 89%

Charcot–Marie–Tooth type 4B demyelinating neuropathy: deciphering the role of MTMR phosphatases

Previtali

Quattrini

Bolino

2007

Expert Rev. Mol. Med.

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Charcot-Marie-Tooth type 4B (CMT4B) is a severe autosomal recessive neuropathy with demyelination and myelin outfoldings of the nerve. This disorder is genetically heterogeneous, but thus far, mutations in myotubularin-related 2 (MTMR2) and MTMR13 genes have been shown to underlie CMT4B1 and CMT4B2, respectively. MTMR2 and MTMR13 belong to a family of ubiquitously expressed proteins sharing homology with protein tyrosine phosphatases (PTPs). The MTMR family, which has 14 members in humans, comprises catalytically active proteins, such as MTMR2, and catalytically inactive proteins, such as MTMR13. Despite their homology with PTPs, catalytically active MTMR phosphatases dephosphorylate both PtdIns3P and PtdIns(3,5)P2 phosphoinositides. Thus, MTMR2 and MTMR13 may regulate vesicular trafficking in Schwann cells. Loss of these proteins could lead to uncontrolled folding of myelin and, ultimately, to CMT4B. In this review, we discuss recent findings on this interesting protein family with the main focus on MTMR2 and MTMR13 and their involvement in the biology of Schwann cell and CMT4B neuropathies.

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Coincidence of two genetic forms of Charcot–Marie–Tooth disease in a single family

Cited by 27 publications

References 9 publications

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

Charcot–Marie–Tooth type 4B demyelinating neuropathy: deciphering the role of MTMR phosphatases

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