Large deletion mutation of <i><scp>SPAST</scp></i> in a multi‐generation family from <scp>S</scp>ardinia

Racis, Loretta; Fabio, Roberto Di; Tessa, Alessandra; Guillot, F.; Storti, Eugenia; Piccolo, F.; Nesti, Claudia; Tedde, Andrea; Pierelli, Francesco; Agnetti, Virgilio; Santorelli, Filippo M.; Casali, Carlo

doi:10.1111/ene.12290

Cited by 4 publications

(8 citation statements)

References 11 publications

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“…At this point, we cannot state if IV-25 will develop any clinical manifestation in the near future or if she is a true not penetrant carrier of the mutation, since her present age is slightly younger than the mean age of onset of motor disturbances in the family. Reduced or no penetrance has repeatedly been described in spastin-related HSP kindred [ 1 , 3 ], including cases from Sardinia [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

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Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred

et al. 2014

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BackgroundThe hereditary spastic paraplegias (HSPs) are pleiomorphic disorders of motor pathway and a large number of affected genes have been discovered. Yet, mutations in SPG4/SPAST represent the most frequent molecular etiology in autosomal dominant (AD) patients and sporadic cases. We describe a large, AD-HSP Sardinian family where 5 out of several living members harbored a novel deletion affecting also the 5′UTR of SPAST and resulting in reduced expression of DPY30, the gene located upstream SPAST in a head-to-head manner.Case presentationA 54-year-old woman manifested leg stiffness at age 39 and required a cane to walk at age 50. Neurological examination disclosed mild spasticity and weakness in the legs, hyperreflexia in all limbs, and bilateral Babinski sign. She also complained of urinary urgency, but no additional neurological symptoms or signs were detected at examination. The clinical examination of 24 additional relatives disclosed three further affected individuals, two men and one woman. In the four symptomatic patients the initial manifestations were walking abnormalities and leg stiffness with a mean age at onset (SD) of 46.75 (5.44) years (range 39–51). The mean disease duration was 13.2 (13.4) years (range 6–35), and it correlated well with clinical severity (SPRS score) (r = 0.975, p = 0.005). One patient was confined to bed and displayed knee and ankle contractures, another case needed a cane to walk, and two individuals were able to walk without aids. Interestingly, a patient had also had a miscarriage during her first pregnancy.Gene testing revealed an heterozygous deletion spanning from the 5′-UTR to intron 4 of SPAST in the affected individuals and in one clinically unaffected woman. In three affected patients, the deletion also determined low mRNA levels of SPAST and DPY30, a component of the Set1-like multiprotein histone methyltransferase complex located upstream, head-to-head with SPAST.ConclusionTogether with data described in a Japanese family, our findings seem to suggest that genes close to spastin might be candidates in modulating the clinical phenotype. This report endorses future research on the role of neighboring genes as potential players in SPG4 disease variability.

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Section: Resultsmentioning

confidence: 99%

“…Analysis of common AD genes associated with HSP used traditional Sanger sequencing and the BigDye 3.1 Chemistry, as reported [ 5 ]. Search for copy number variation and gene deletion/duplication adopted reported array-comparative genomic hybridization (aCGH) and multiple ligation-dependent probe amplication (MLPA) methodologies [ 10 ].…”

Section: Methodsmentioning

confidence: 99%

Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred

et al. 2014

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“…Deletions in SPAST gene are common in hereditary spastic paraplegia [ 35 ]. However, the high phenotypic variability of the disease makes clinical evaluation and molecular characterization challenging, especially when proximal muscle weakness in the limbs and minimal neurological signs are present [ 36 ], as in patient XII. In this case, identification of the SPAST deletion provided the molecular diagnosis in her family, increasing the number of described cases.…”

Section: Discussionmentioning

confidence: 99%

“…In this case, identification of the SPAST deletion provided the molecular diagnosis in her family, increasing the number of described cases. As previously reported, the presence of an asymptomatic carrier of a spastin deletion may be considered a reduced penetrance of the disorder [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients

Giugliano

Savarese

Garofalo

et al. 2018

Genes

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Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5–9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.

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“…Neurology encompasses an enormous spectrum of disorders, probably the largest of all medical disciplines . Neurological complications of other system diseases are common.…”

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confidence: 99%

Neurology in evolution 2014–2015

Schapira¹

2015

Euro J of Neurology

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Large deletion mutation of SPAST in a multi‐generation family from Sardinia

Abstract: A focus on spasticity, increased tendon reflexes and Babinski sign, more than on weakness, could help clinicians to promote early diagnosis in asymptomatic carriers of SPAST deletions.

Cited by 4 publications

References 11 publications

Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred

Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred

Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients

Neurology in evolution 2014–2015

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