“…The present study, which addressed “many genes in many patients” and investigated practically all the known genes related to HSP and similar motor neuron disorders, was expected to give a higher positive diagnostic yield than it actually did; furthermore, at least 60% of the patients were investigated underwent NGS testing as a first-tier approach, in order to reflect modern procedures in diagnostic laboratories. However, initial expectations notwithstanding, the overall findings showed a 29% diagnostic yield, a rate similar to those reported in other studies, including more recent ones that present population-specific data (44, 45). There are two possible reasons for this unexpected result.…”
Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity—there are over 80 potential disease-associated genes—and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.
“…The present study, which addressed “many genes in many patients” and investigated practically all the known genes related to HSP and similar motor neuron disorders, was expected to give a higher positive diagnostic yield than it actually did; furthermore, at least 60% of the patients were investigated underwent NGS testing as a first-tier approach, in order to reflect modern procedures in diagnostic laboratories. However, initial expectations notwithstanding, the overall findings showed a 29% diagnostic yield, a rate similar to those reported in other studies, including more recent ones that present population-specific data (44, 45). There are two possible reasons for this unexpected result.…”
Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity—there are over 80 potential disease-associated genes—and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.
“…CADD scores (vs 1.3) and population frequencies were obtained through https://cadd.gs.washington.edu/ and http://exac.broadinstitute.org, respectively. Conservation was determined using ensemble alignments M mammals, F fish, DM Drosophila melanogaster , CE C.elegans, ni not informative a This family has been described [15]Fig. 1Schematic representation of the KIF1A protein with variants in dominant spastic paraplegia.…”
Section: Resultsmentioning
confidence: 99%
“…A filter for a ‘movement disorders’ gene panel was applied. This panel consists of ∼300 genes implicated in various forms of cerebellar ataxia, HSP, genetic choreas, and other hyperkinetic movement disorders [15] and is available from our website (https://www.radboudumc.nl/en/patientenzorg/onderzoeken/exome-sequencing-diagnostics/exomepanelspreviousversions/movement-disorders). The single nucleotide variant data were filtered by [1] frequency (<5% dbSNP, <1% in house database, gnomAD, EXAC [16]) [2] nucleotide and amino acid conservation and [3] exon/intronic position (−20 till +8).…”
Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly ‘pure’ spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0–57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6–7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.
“…More than 100 genes are known to cause autosomal dominant, autosomal recessive, and X-linked forms of HSP; a subset of these genes have been cataloged by OMIM (www.omim.org) as Spastic Paraplegia Genes (SPG1–SPG80). Still, mutations in known HSP genes explain only about two-third of cases 21,23,24 . Mutations in novel HSP genes as well as novel mutation types that cannot be reliably detected or interpreted by current technology and prediction algorithms are likely to contribute to this ‘missing heritability’ in HSPs.…”
Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.
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