SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals

Bowen, Barry M.; Truty, Rebecca; Aradhya, Swaroop; Bristow, Sara L.; Johnson, Britt; Morales, Ana; Tan, Christopher; Westbrook, M Jody; Winder, Thomas; Chávez, Juan C.

doi:10.3389/fneur.2021.663911

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…To date, together with our six newly described patients, a total of 44 patients carrying c.859G>C have been reported worldwide, including a patient recently detected by newborn screening [ 21 , 22 , 23 , 25 , 31 , 32 , 33 , 34 ]. In general population databases, the c.859G>C variant is reported at a frequency of approximately 0.3% with 132 homozygotes detected [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Blasco-Pérez

Costa-Roger

Leno-Colorado

et al. 2022

IJMS

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Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype–phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype–phenotype correlations and improve prognostic outcomes.

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Section: Discussionmentioning

confidence: 99%

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Blasco-Pérez

Costa-Roger

Leno-Colorado

et al. 2022

IJMS

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“…With the two variants identified recently (the frameshift and the currently reported novel splice site), under the hypothesis that there are no other Cypriot cases that have been diagnosed by a foreign country centre, this percentage is ~19% in our population, which is probably much higher than in other populations To our knowledge, expect for a recent study in Brazil referring to a percentage of 10.7% of compound heterozygous intragenic variants identified by next generation sequencing without excluding the SMN2 interference ( 26 ), the reported percentages in other populations do not exceed 5% [i.e. France (1.3%) ( 3 ), Germany (3.4%) ( 27 ), Spain (3.0–3.3%) ( 28 , 29 ), Italy (3.2%) ( 30 ), Korea (3.0%) ( 31 ), United States (3.8% including possible SMN2 variants) ( 32 )].…”

Section: Discussionmentioning

confidence: 99%

Spinal muscular atrophy type I associated with a novel SMN1 splicing variant that disrupts the expression of the functional transcript

Votsi,

Koutsou,

Ververis

et al. 2023

Front. Neurol.

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IntroductionSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by pathogenic variants in the SMN1 gene. The majority of SMA patients harbor a homozygous deletion of SMN1 exon 7 (95%). Heterozygosity for a conventional variant and a deletion is rare (5%) and not easily detected, due to the highly homologous SMN2 gene interference. SMN2 mainly produces a truncated non-functional protein (SMN-d7) instead of the full-length functional (SMN-FL). We hereby report a novel SMN1 splicing variant in an infant with severe SMA.MethodsMLPA was used for SMN1/2 exon dosage determination. Sanger sequencing approaches and long-range PCR were employed to search for an SMN1 variant. Conventional and improved Real-time PCR assays were developed for the qualitative and quantitative SMN1/2 RNA analysis.ResultsThe novel SMN1 splice-site variant c.835-8_835-5delinsG, was identified in compound heterozygosity with SMN1 exons 7/8 deletion. RNA studies revealed complete absence of SMN1 exon 7, thus confirming a disruptive effect of the variant on SMN1 splicing. No expression of the functional SMN1-FL transcript, remarkable expression of the SMN1-d7 and increased levels of the SMN2-FL/SMN2-d7 transcripts were observed.DiscussionWe verified the occurrence of a non-deletion SMN1 variant and supported its pathogenicity, thus expanding the SMN1 variants spectrum. We discuss the updated SMA genetic findings in the Cypriot population, highlighting an increased percentage of intragenic variants compared to other populations.

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“…The NGS technique, as a relatively new method, has been developed and gradually applied to the determination of SMN1 gene copy number, even for SMA carrier screening 18 , 19 , 31 , 39 , 40 . It displayed good performance not only for the detection of homozygous deletion but also for heterozygous deletion in this study.…”

Section: Discussionmentioning

confidence: 99%

Next generation sequencing is a highly reliable method to analyze exon 7 deletion of survival motor neuron 1 (SMN1) gene

Zhao

Wang

Xin

et al. 2022

Sci Rep

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Spinal muscular atrophy (SMA) is one of the most common and severe genetic diseases. SMA carrier screening is an effective way to identify couples at risk of having affected children. Next-generation sequencing (NGS)-based expanded carrier screening could detect SMN1 gene copy number without extra experiment and with high cost performance. However, its performance has not been fully evaluated. Here we conducted a systematic comparative study to evaluate the performance of three common methods. 478 samples were analyzed with multiplex ligation probe amplification (MLPA), real-time quantitative polymerase chain reaction (qPCR) and NGS, simultaneously. Taking MLPA-based results as the reference, for 0 copy, 1 copy and ≥ 2 copy SMN1 analysis with NGS, the sensitivity, specificity and precision were all 100%. Using qPCR method, the sensitivity was 100%, 97.52% and 94.30%, respectively; 98.63%, 95.48% and 100% for specificity; and 72.72%, 88.72% and 100% for precision. NGS repeatability was higher than that of qPCR. Moreover, among three methods, NGS had the lowest retest rate. Thus, NGS is a relatively more reliable method for SMN1 gene copy number detection. In expanded carrier screening, compared with the combination of multiple methods, NGS method could reduce the test cost and simplify the screening process.

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SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals

Cited by 8 publications

References 35 publications

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Spinal muscular atrophy type I associated with a novel SMN1 splicing variant that disrupts the expression of the functional transcript

Next generation sequencing is a highly reliable method to analyze exon 7 deletion of survival motor neuron 1 (SMN1) gene

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