The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives

Stevanin, Giovanni

doi:10.3389/fgene.2021.638730

Cited by 11 publications

(14 citation statements)

References 166 publications

(240 reference statements)

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“…The clinical and genetic heterogeneity of the disease, as well as the small number of families in some HSP types, makes it difficult to describe accurate genotype–phenotype associations. In the “next generation era” the rate of diagnosis using WES, especially when targeted, is about 45%–75% in HSP (Novarino et al, 2014; Saputra & Kumar, 2021; Yahia & Stevanin, 2021). Growing data obtained through next generation sequencing (NGS) techniques in the last decade has provided some insight into genotype–phenotype assessment.…”

Section: Discussionmentioning

confidence: 99%

“…In the "next generation era" the rate of diagnosis using WES, especially when targeted, is about 45%-75% in HSP (Novarino et Abbreviations: EMG/NCV, electromyography/nerve conduction velocity; II, intellectual impairment; MRI, magnetic resonance imaging; N/A, not available. Kumar, 2021;Yahia & Stevanin, 2021). Growing data obtained through next generation sequencing (NGS) techniques in the last decade has provided some insight into genotype-phenotype assessment.…”

Section: Discussionmentioning

confidence: 99%

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Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias

Ölmez¹,

Çetin

Karaer

2022

American J of Med Genetics Pt A

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Hereditary spastic paraplegias (HSP) are a group of inherited, neurodegenerative disorders characterized by progressive gait impairment, lower extremity spasticity and increased patellar reflexes. More than 80 types of HSP have been defined to date. In complicated forms, lower limb spasticity and gait impairment is accompanied by an additional neurological finding. Autosomal recessive (AR) HSPs are usually identified in complicated forms and occur more frequently in countries where consanguineous marriage is more widespread. Next generation sequencing techniques, developed in the last decade, have led to the identification of many new types of HSP and reduced the “diagnostic odyssey.” Whole exome sequencing (WES) can diagnose up to 75% of undiagnosed HSP patients. Targeted genetic analysis with good clinical phenotyping gives the best diagnostic yields for rare diseases. Clinical heterogeneity is prominent in AR complicated HSP. However, some clinical features complicating the disease or magnetic resonance imaging findings, including thin corpus callosum or white matter abnormalities, can help to distinguish some types. AR spastic paraplegia type 64 (SPG64) is a very rare HSP, caused by a mutation in the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) gene, first described in 2014. To date only nine patients from five families have been reported. We present two siblings with a novel pathogenic variant in ENTPD1, diagnosed by WES, as the sixth published family. We propose that early onset in childhood, cognitive impairment, dysarthria/anarthria, dystonia and areflexia may be the distinctive features of SPG64 and more clinical evidence from families with pathogenic ENTPD1 variants is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias

Ölmez¹,

Çetin

Karaer

2022

American J of Med Genetics Pt A

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“…Intellectual impairment, cerebellar ataxia, neuropathy, and skeletal deformities are common presentations complicating HSP ( 2 ). The advent of next-generation sequencing (NGS) has revolutionized HSP diagnosis and emphasized its extreme genetic heterogeneity broadening the list of the currently identified HSP-causing genes to include more than 80 genes ( 3 ). The HSP global prevalence has been estimated as 1.8/10 5 ( 4 ), a value probably underestimated because of the lack of accessibility to new diagnostic technologies ( 3 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

et al. 2021

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Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity.Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies.Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.Conclusion:ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

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“…Among the genetically de ned CA cases, tandem expansions of nucleotide repeats account for nearly 30-40% of the disease burden, while conventional variants add another half to the causal factor list 5 . Whole exome sequencing (WES) as a high throughput tool for detection of all coding variants, has been found to be more e cient than other genetic tools at improving diagnostic yield and enabling novel gene discoveries [6][7][8] . Our previous study in autosomal recessive CA (ARCA) families has enabled us to identify both, already reported as well as novel variants in typical and atypical ataxia genes with a much higher diagnostic yield (56%) using WES, as compared to targeted resequencing 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Integrated whole exome sequencing and functional approach delineate genetic heterogeneity in cerebellar ataxias

Kumari

Uppilli

Shakya

et al. 2021

Preprint

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PurposeDisease deconvolution in heterogeneous cerebellar ataxias (CAs) needs a focussed approach to overcome the diagnostic challenges. A diverse clinical presentation with over 100 reported genetic loci, in addition to the various challenges associated with genotype-phenotype correlation complicate the genetic diagnosis in 40-60% of the CA cases that remain uncharacterized. We present here an integrated whole exome sequencing combined with a functional validation approach to delineate the genetic etiology in Indian CA patients.MethodA total of 50 familial and sporadic progressive CA families (negative for CNG expansion) including 101 subjects were recruited for this study. Index patients from 50 families were subjected to singleton whole exome sequencing (S-WES). Family-based WES (F-WES) was carried out for seven S-WES selected families. Protein simulation and docking studies were performed for seven genetic variants identified through WES. A Cell line-based model was used to assess disease signatures for variants in KCNC3 and a new candidate gene, SPTB.ResultsClinically relevant variants identified in 70% (35/50) of the selected families. We achieved a 50% (25/50) definitive diagnostic yield and 14% (7/50) probable diagnostic yield while 6% (3/50) of the families showed variants of uncertain significance. We prioritized compound heterozygous variants in a candidate gene, SPTB for cerebellar ataxia with hereditary spherocytosis. Lymphoblastoid cell line derived from a patient with a KCNC3 variant showed altered disease signatures with induced ROS and elevated unfolded protein response markers at the basal level.ConclusionOur results highlight an extensive experimental design for the genetic diagnosis of CA. Through targeted analysis of ataxia phenotype-derived gene panel in S-WES, new gene identification through F-WES, and revaluation of unsolved families’ WES data, we identified novel, reported and other clinically relevant variants in CA patients. Bioinformatic protein modeling along with the cellular insights into the pathogenicity of novel variants enabled delineation of genetic diagnostics and enhanced the mechanistic understanding of CAs.

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The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives

Cited by 11 publications

References 166 publications

Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias

Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias

Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

Integrated whole exome sequencing and functional approach delineate genetic heterogeneity in cerebellar ataxias

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