Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

Iqbal, Zafar; Rydning, Siri Lynne; Wedding, Iselin Marie; Koht, Jeanette; Pihlstrøm, Lasse; Rengmark, Aina; Henriksen, Sandra Pilar; Tallaksen, Chantal; Toft, Mathias

doi:10.1371/journal.pone.0174667

Cited by 48 publications

(42 citation statements)

References 45 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This same variant was also observed in a multigeneration Sicilian family with a more variable phenotype, complicated in some members by psychomotor delay, hand amyotrophy, and sensory abnormalities 12. Finally, Iqbal et al 13. found that both c.80T>C, p.Ile27Thr and c.22G>A, p.Val8Met were associated with pure HSP in multigeneration families.…”

Section: Introductionmentioning

confidence: 65%

Multigeneration family with dominant SPG30 hereditary spastic paraplegia

Roda

Schindler

Blackstone

2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

show abstract

Section: Introductionmentioning

confidence: 65%

Multigeneration family with dominant SPG30 hereditary spastic paraplegia

Roda

Schindler

Blackstone

2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…Many disease-associated mutations have been found in the motor domain of KIF1A (24,26,27). We noticed that the gain-of-function V6I mutation in unc-104, identified in our C. elegans genetic screen, is equivalent to the dominant SPG-associated mutation, V8M, in human KIF1A (12,27) (Figs 1A and B). Our previous data revealed that worm UNC-104(V6I) and mouse KIF1A(V8I) are constitutive active in worm neurons and COS-7 cells, respectively (12).…”

Section: Not All Disease-associated Mutations In Kif1a Are Loss-of-fumentioning

confidence: 77%

“…Many mutations in the motor domain of KIF1A are associated with neuronal diseases, leading to both the pure and complicated forms of SPG, as well as mental retardation (24,26,27). However, it remained unknown why different mutations cause different types of diseases.…”

Section: Discussionmentioning

confidence: 99%

Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors

Chiba¹,

Chen

Arai

et al. 2019

Preprint

View full text Add to dashboard Cite

KIF1A is a kinesin-family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules. In humans, more than ten point mutations in KIF1A are associated with the motor neuron disease, hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus, a clear molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the pure form of spastic paraplegia hyperactivate motility of the KIF1A motor. Introduction of the corresponding mutations into Caenorhabditis elegans KIF1A homologue unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs. Our data reveal that hyper-activation of kinesin motor activity, rather than its loss-of-function, is a novel cause of motor neuron disease in humans. Significance StatementAnterograde axonal transport supplies organelles and protein complexes throughout axonal processes to support neuronal morphology and function. It has been observed that reduced anterograde axonal transport is associated with neuronal diseases. In contrast, here we show that particular disease-associated mutations in KIF1A, an anterograde axonal motor for synaptic vesicle precursors, induce hyperactivation of KIF1A motor activity and increased axonal transport of synaptic vesicle precursors. Our results advance the knowledge of the regulation of motor proteins and axonal transport and cell biology of motor neuron diseases.

show abstract

“…Studies using NGS in disease-specific contexts have reported high diagnostic yields ranging from 19% for spastic paraplegia to 60% for neuromuscular disorders. [9][10][11] Historically, copy number variant (CNV) analysis has been limited to only a narrow group of genes 12 or has not been routinely performed in neuromuscular genetic testing. 9,13,14 Recently, the accurate detection of CNVs alongside sequence variants by NGS in a single assay has enabled more comprehensive, more affordable, and faster genetic analysis with a single sample.…”

mentioning

confidence: 99%

Clinical utility of multigene analysis in over 25,000 patients with neuromuscular disorders

et al. 2020

View full text Add to dashboard Cite

ObjectiveMolecular genetic testing for hereditary neuromuscular disorders is increasingly used to identify disease subtypes, determine prevalence, and inform management and prognosis, and although many small disease-specific studies have demonstrated the utility of genetic testing, comprehensive data sets are better positioned to assess the complexity of genetic analysis.MethodsUsing high depth-of-coverage next-generation sequencing (NGS) with simultaneous detection of sequence variants and copy number variants (CNVs), we tested 25,356 unrelated individuals for subsets of 266 genes.ResultsA definitive molecular diagnosis was obtained in 20% of this cohort, with yields ranging from 4% among individuals with congenital myasthenic syndrome to 33% among those with a muscular dystrophy. CNVs accounted for as much as 39% of all clinically significant variants, with 10% of them occurring as rare, private pathogenic variants. Multigene testing successfully addressed differential diagnoses in at least 6% of individuals with positive results. Even for classic disorders like Duchenne muscular dystrophy, at least 49% of clinically significant results were identified through gene panels intended for differential diagnoses rather than through single-gene analysis. Variants of uncertain significance (VUS) were observed in 53% of individuals. Only 0.7% of these variants were later reclassified as clinically significant, most commonly in RYR1, GDAP1, SPAST, and MFN2, providing insight into the types of evidence that support VUS resolution and informing expectations of reclassification rates.ConclusionsThese data provide guidance for clinicians using genetic testing to diagnose neuromuscular disorders and represent one of the largest studies demonstrating the utility of NGS-based testing for these disorders.

show abstract

Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

Cited by 48 publications

References 45 publications

Multigeneration family with dominant SPG30 hereditary spastic paraplegia

Multigeneration family with dominant SPG30 hereditary spastic paraplegia

Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors

Clinical utility of multigene analysis in over 25,000 patients with neuromuscular disorders

Contact Info

Product

Resources

About