scholarly journals Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy

2020 ◽  
Vol 6 (5) ◽  
pp. e505
Author(s):  
Rodrigo de Holanda Mendonça ◽  
Ciro Matsui ◽  
Graziela Jorge Polido ◽  
André Macedo Serafim Silva ◽  
Leslie Kulikowski ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Copy Number ◽  
Clinical Phenotype ◽  
Muscular Atrophy ◽  
Large Population ◽  
Survival Motor Neuron ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Exon 1 ◽  
Compound Heterozygous Variants

ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

scholarly journals Adult-Onset Spinal Muscular Atrophy due to Mutations in the VRK1 Gene

2021 ◽  
Vol 7 (4) ◽  
pp. e599
Author(s):  
Angela Sung ◽  
Paolo Moretti ◽  
Aziz Shaibani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Gene Mutations ◽  
Molecular Data ◽  
Clinical Syndrome ◽  
Compound Heterozygous ◽  
Adult Onset ◽  
Pathogenic Variants ◽  
Neurologic Disorders ◽  
Progressive Weakness

ObjectiveTo expand our knowledge of the range of clinical phenotypes associated with vaccinia-related kinase 1 (VRK1) gene mutations.MethodsWe present clinical and molecular data of 2 individuals with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy without pontocerebellar atrophy.ResultsGenetic testing revealed likely pathogenic variants in the VRK1 gene in both subjects. One individual carried homozygous p.R321C (c.961 C>T), likely pathogenic variants. The other carried compound heterozygous p.V236M (c.706 G>A) and p.R321C (c.961 C>T), likely pathogenic variants. Notably, both patients were of Hispanic descent.ConclusionsWe report 2 cases with VRK1 mutations presenting as adult-onset spinal muscular atrophy without pontocerebellar hypoplasia and review the current literature of similar cases. Our report expands the clinical spectrum of neurologic disorders associated with VRK1 mutations.

scholarly journals Cloning, Characterization, and Copy Number of the Murine Survival Motor Neuron Gene: Homolog of the Spinal Muscular Atrophy-Determining Gene

1997 ◽  
Vol 7 (4) ◽  
pp. 339-352 ◽  
Author(s):  
Christine J. DiDonato ◽  
Xiao-Ning Chen ◽  
David Noya ◽  
Julie R. Korenberg ◽  
Joseph H. Nadeau ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Copy Number ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Gene

Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity

2002 ◽  
Vol 249 (9) ◽  
pp. 1211-1219 ◽  
Author(s):  
Yosuke Harada ◽  
Retno Sutomo ◽  
Ahmad Hamim Sadewa ◽  
Tomoko Akutsu ◽  
Yasuhiro Takeshima ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Copy Number ◽  
Clinical Phenotype ◽  
Muscular Atrophy

scholarly journals Mutation analysis and prenatal diagnosis of 419 cases of Spinal Muscular Atrophy in China

2020 ◽  
Author(s):  
YingJie Sun ◽  
Xiangdong Kong ◽  
Xuechao Zhao ◽  
Zhenhua Zhao
Keyword(s):  
Prenatal Diagnosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Chorionic Villus ◽  
Genetic Diagnosis ◽  
Point Mutations ◽  
Homozygous Deletion ◽  
Compound Heterozygous ◽  
Prenatal Genetic Diagnosis ◽  
Compound Heterozygous Variants

Abstract Background Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease, which is caused by mutations of the survival motor neuron 1 (SMN1) gene. At present, the gene therapy medicine for SMA, i.e. , Spinraza (Nusinersen), has been approved by the FDA, bringing hope to SMA patients and families. In this study, we analyzed the deletion of SMN gene in patients suspected of SMA, and performed prenatal genetic diagnosis of SMA. Methods In this study, we collected the peripheral blood of 419 probands and their parents who were treated in the genetic counseling clinic at our hospital from January 2010 to September 2019, and extracted DNA from the blood samples for analysis. Patients who were diagnosed with SMA were first tested by MLPA. The patients with negative MLPA results were further analysed with long-range PCR combined with nest PCR and validated by Sanger sequencing to look for point mutations. In 293 families, pregnant women were subjected to chorionic villus or amniotic fluid sampling for prenatal genetic diagnosis depending on gestational weeks. In addition to the above methods used for genetic diagnosis, we also used QF-PCR in all prenatal diagnoses, which can help detect the presence of trisomy of chromosome while eliminating maternal contamination. Results 1. Homozygous deletion of SMN1 exon 7 was detected in 96.40% (404/419) of patients. Homozygous deletion of SMN1 exon 7 alone was detected in 15 patients (3.60%). 2. In total, 10 point mutations were detected in the 15 pedigrees. Five of these variants have not been previously reported in the literature. 3. Among the 293 pedigrees that underwent one prenatal diagnosis, 118 foetuses were normal, 149 foetuses were carriers of heterozygous variants, and the remaining 72 foetuses harboured compound heterozygous variants or homozygous variants. 4. In all prenatal diagnoses, we found one 21-trisomy fetus by QF-PCR. Couples whose foetuses were normal or carriers continued the pregnancy, whereas couples whose foetuses harboured compound heterozygous variants or homozygous variants decided to terminate the pregnancy. The follow-up results were consistent with the prenatal diagnosis.

scholarly journals Spinal muscular atrophy (5qSMA): best practice of diagnostics, newborn screening and therapy

2020 ◽  
Vol 32 (3) ◽  
pp. 263-272
Author(s):  
Katja Eggermann ◽  
Dieter Gläser ◽  
Angela Abicht ◽  
Brunhilde Wirth
Keyword(s):  
Spinal Muscular Atrophy ◽  
Newborn Screening ◽  
Best Practice ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Genetic Defect ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Compound Heterozygous ◽  
Common Mutation

Abstract Proximal spinal muscular atrophy (SMA) is an autosomal-recessive inherited neuromuscular disorder caused by the degeneration of alpha motor neurons in the anterior horn of the spinal cord. Patients show hypotonia, muscular atrophy and weakness of voluntary proximal muscles. SMA is one of the most common genetic diseases, with a frequency of about 1 in 7,000 newborns in Germany. The vast majority of patients carry a homozygous deletion of exons 7 and 8 of the survival motor neuron (SMN) 1 gene on chromosome 5q13.2; only about 3–4 % of patients are compound heterozygous for this common mutation and an additional subtle mutation in SMN1. The severity of the disease is mainly influenced by the copy number of the highly homologous SMN2. Since the discovery of the underlying genetic defect 25 years ago, both the diagnostics of SMA and its treatment have undergone constant and in recent times rapid improvements. SMA has become one of the first neuromuscular disorders with effective therapies based on gene targeted strategies such as splice correction of SMN2 via antisense oligonucleotides or small molecules or gene replacement therapy with a self-complementary adeno-associated virus 9 expressing the SMN1-cDNA. With the availability of treatment options, which are most effective when therapy starts at a pre-symptomatic stage, a newborn screening is indispensable and about to be introduced in Germany. New challenges for diagnostic labs as well as for genetic counsellors are inevitable. This article aims at summarising the current state of SMA diagnostics, treatment and perspectives for this disorder and offering best practice testing guidelines to diagnostic labs.

scholarly journals The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

2021 ◽  
Vol 22 (16) ◽  
pp. 9029
Author(s):  
Mar Costa-Roger ◽  
Laura Blasco-Pérez ◽  
Ivon Cuscó ◽  
Eduardo F. Tizzano
Keyword(s):  
Motor Neuron ◽  
Copy Number ◽  
Muscular Atrophy ◽  
Clinical Investigation ◽  
Survival Motor Neuron ◽  
Disease Evolution ◽  
Pathogenic Variants ◽  
Technical Issues ◽  
Discordant Genotype

After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.

scholarly journals Novel compound heterozygous pathogenic variants in ASCC1 in a Chinese patient with spinal muscular atrophy with congenital bone fractures 2 : evidence supporting a "Definitive" gene-disease relationship

2019 ◽  
Author(s):  
Weiliang Lu ◽  
Mingxing Liang ◽  
Jiasun Su ◽  
Jin Wang ◽  
Lingxiao Li ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Exome Sequencing ◽  
Disease Gene ◽  
Bone Fractures ◽  
Muscular Atrophy ◽  
Chinese Patient ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Limited Spectrum

Abstract Background: A very limited spectrum of ASCC1 pathogenic variants had been reported in five (mostly consanguineous) families with spinal muscular atrophy with congenital bone fractures 2 [OMIM #616867] since 2016. Methods:A proband from a non-consanguineous Chinese family presented with neonatal severe hypotonia, respiratory distress, muscle weakness and atrophy, as well as congenital bone fractures was examined by exome sequencing. Results: A compound heterozygosity of a nonsense (c.932C>G ,p.Ser311Ter) and an exon 5 deletion in ASCC1 segregating with phenotypes was detected, both variants are novel and pathogenic. Since ASCC1 is a relative new disease gene, we performed the gene curation following ClinGen SOP. The existing evidence is sufficient to support a "Definitive" level of disease-gene relationship. Conclusion: This case report expended the mutation spectrum of ASCC1 and support the notion that this novel disease also occur in outbreed populations and this is a rare disease but may still be underdiagnosed due to its perinatal lethal outcomes. Keywords: spinal muscular atrophy with congenital bone fractures 2; ASCC1 ; compound heterozygous; gene curation; exome sequencing

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