Evidence of mosaicism in SPAST variant carriers in four French families

Angelini, C.; Goizet, Cyril; Camu, William; Depienne, Christel; Héron, Bénédicte; Kol, Bophara; Guillaud‐Bataille, Marine; Pennamen, Perrine; Rooryck, Caroline; Scherer-Gagou, Clarisse; Tissier, Laurène; Stevanin, Giovanni; LeGuern, Eric; Banneau, Guillaume

doi:10.1038/s41431-021-00847-4

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…This has particular importance as these deletions are relatively frequent in SPG4 (Beetz et al, 2006;Depienne et al, 2007;Newton et al, 2018). Finally, somatic mosaicism was shown to be a potential source of variant expressivity in SPAST mutation carriers (Angelini et al, 2021). However, the reduced penetrance of several variants in HSP genes still remains to be explained with the nature of the variants, their impact on protein expression/stability, the presence of compensatory protein or partners yet to be explored.…”

Section: Genetic Diagnosis: Approaches Yield and Gap In Genetic Etiologymentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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Section: Genetic Diagnosis: Approaches Yield and Gap In Genetic Etiologymentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Clinical genetics—it’s polygenic

McNeill

2021

Eur J Hum Genet

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A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

Shen¹,

Zhang²,

Li³

et al. 2022

Ann Transl Med

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Background: Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 purely HSP patients in Yunnan Province.Methods: Whole-exome sequencing (WES) was applied to 2 HSP patients and 1 control patient to screen out the candidate gene variants. Then, filtration and verification of these pathological variants were performed by Sanger sequencing.Results: After the raw data were filtered, two genes with novel variations (SPAST: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; DNAJC16: c.718 C>T, p.Q240X, Ref Seq NM_015291) were identified. The accession numbers of the genes in the ClinVar database were SCV001573094 and SCV001573804, respectively. One gene with a reported single nucleotide polymorphism (CPT1C: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel SPAST gene (protein: Spastin) variant leading to a predicted premature termination and an 18% deletion of the SPAST/spastic paraplegia type 4 (SPG4) protein was confirmed to exist only in affected individuals. The candidate CPT1C and DNAJC16 variants were verified in almost all HSP patients, with one exception.Conclusions: Considering that the clinical symptoms and time of onset of HSP are highly heterogeneous, the SPAST as a genotype-phenotype cosegregated variant might be the causative gene of this pedigree, and the other two variants might present cumulative risks to the occurrence and progression of HSP. These three candidate genes with or without novel variants may be potential contributors to disease onset, and therefore useful diagnostic and therapeutic biomarkers. Further research is required to confirm the functions of these genes.

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Evidence of mosaicism in SPAST variant carriers in four French families

Cited by 3 publications

References 17 publications

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Clinical genetics—it’s polygenic

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

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