Genetic heterogeneity of motor neuropathies

Bánsági, Boglárka; Griffin, Helen; Whittaker, Roger G.; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah E.; Ramesh, Venkateswaran; Frankó, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F.; Horvath, Rita

doi:10.1212/wnl.0000000000003772

Cited by 85 publications

(111 citation statements)

References 40 publications

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“…3 Recent studies have begun to show the impact of this new technology for genetically heterogeneous disorders, such as IPN. [4][5][6][7][8][9][10] To further inform the diagnostic utility of WES for this highly heterogeneous group of disorders, we performed WES on a cohort of 50 undiagnosed IPN families with 1 or more affected individuals. Data was initially analyzed for variants in genes known to cause IPN, and unsolved families were subsequently analyzed for novel IPN disease-gene relationships.…”

Section: Funding Informationmentioning

confidence: 99%

Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

et al. 2017

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The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery.

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Section: Funding Informationmentioning

confidence: 99%

Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

et al. 2017

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“…For example, differentiation of dHMNs from distal myopathies can be difficult due to similar muscular involvement and disease course (Komlosi et al., ). In some families, an HMN can be the main clinical feature among several clinical manifestations, such as ataxia, spasticity, growth retardation, and dysmorphic features (Bansagi et al., ). The overlap between neuropathies and myopathies is also shown by myopathic individuals carrying nonsense mutations in NEFL gene, formerly linked to neurogenic disorders (Agrawal et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, differentiation of dHMNs from distal myopathies can be difficult due to similar muscular involvement and disease course (Komlosi et al, 2014). In some families, an HMN can be the main clinical feature among several clinical manifestations, such as ataxia, spasticity, growth retardation, and dysmorphic features (Bansagi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

et al. 2018

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Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate.

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“…Adult‐onset patients usually present with a slowly progressive, predominantly distal, muscle weakness and atrophy as the main manifestation, termed distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (dSMA) . However, additional clinical signs have also been described …”

Section: Introductionmentioning

confidence: 99%

Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

et al. 2020

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Background Adult‐onset hereditary motor neuropathies are caused by mutations in multiple genes. Mutations within the vaccinia‐related kinase 1 (VRK1) gene were associated with a wide spectrum of recessively inherited motor neuropathies, characterized by childhood to early adulthood age of onset and an occasionally non‐lower motor neuron involvement. Methods We describe two patients with adult‐onset (aged 48 and 40 years) length‐dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent. One also demonstrated mild nocturnal respiratory difficulty and sensory symptoms. Whole‐exome sequencing (WES) was performed. Results A homozygous mutation in VRK1 (c.1160G>A (p.Arg387His)), shared by both patients, was identified. This rare mutation segregated with the disease in the two families, and was absent in 120 controls of Jewish Moroccan origin. Conclusions Our findings support VRK1 as a causative gene for adult‐onset distal hereditary motor neuropathy, and indicate its relevance for evaluation of individuals with similar motor impairment.

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Genetic heterogeneity of motor neuropathies

Cited by 85 publications

References 40 publications

Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

Identification of a homozygous VRK1 mutation in two patients with adult‐onset distal hereditary motor neuropathy

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