A homozygous double mutation in <i><scp>SMN</scp>1</i>: a complicated genetic diagnosis of <scp>SMA</scp>

Kirwin, Susan M.; Vinette, Kathy M. B.; Gonzalez, Iris L.; Abdulwahed, Hind Al; Al‐Sannaa, Nouriya; Funanage, Vicky L.

doi:10.1002/mgg3.10

Cited by 19 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These standards were generated from genomic DNA extracted from blood specimens, with copy numbers assessed by QCEFA (Kirwin et al., 2013). One of these reference samples (SDC1) could not be accurately accessed for SMN2 copy number using QCEFA.…”

Section: Resultsmentioning

confidence: 99%

“…The assay conditions were first tested on SMN1 and SMN2 reference standards (n = 7) obtained from the Clinical Laboratory Improvement Amendments (CLIA)certified Molecular Diagnostics Laboratory at N/AIDHC. These standards were generated from genomic DNA extracted from blood specimens, with copy numbers assessed by QCEFA (Kirwin et al, 2013). One of these reference samples (SDC1) could not be accurately accessed for SMN2 copy number using QCEFA.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous assays have been developed to quantify SMN2 copy number in DNA samples from SMA patients. These assays include radioactive PCR (Coovert et al., 1997), quantitative—or real-time PCR (qPCR)––(Feldkötter et al., 2002; Anhuf et al., 2003; Gómez-Curet et al., 2007), competitive PCR/primer extension (Gérard et al., 2004), denaturing high-performance liquid chromatography (Su et al., 2005), multiplex ligation-dependent probe amplification (Huang et al., 2007), quantitative capillary electrophoresis fragment analysis (QCEFA, Kirwin et al., 2013) and short-amplicon melt profiling (Dobrowolski et al., 2012). An important limitation of these established PCR-based copy number assays is the requirement for a parallel-run calibration curve to assign a breakpoint necessary that identifies placement of an ordinal SMN2 value.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

Stabley

Harris

Holbrook

et al. 2015

Molec Gen & Gen Med

Self Cite

View full text Add to dashboard Cite

Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

Stabley

Harris

Holbrook

et al. 2015

Molec Gen & Gen Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…One patient with typical SMA Type II showed two SMN1 copies without any intragenic mutations. Nondeleted patients with homozygous intragenic mutations have been reported in consanguineous families but it is very unlikely in a non-consanguineous family [11,12] Fig. 1 The frequency of genotypes in Cypriot SMA patients.…”

Section: Discussionmentioning

confidence: 99%

Genetic findings of Cypriot spinal muscular atrophy patients

et al. 2015

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families.

show abstract

“…Although, more than 60 subtle mutations of SMN1 gene have been reported worldwide [22], homozygous subtle mutations are very rarely reported in patients with SMA. Kirwin et al reported homozygous double mutation in a SMA patient [29] and Rad et al reported homozygous point mutation (c.549delC at exon 5) which resulted in fame-shift on SMN1 gene in a SMA type I patient [30].These reports imply that although DNA sequencing is routinely carried out on SMA patient with only one copy of SMN1 gene, it should also be carried out in patients with clinical diagnosis of SMA who show even two copies of SMN1 gene [31].…”

Section: Mutation Spectrum Of Smn1 Genementioning

confidence: 99%

Mutation Spectrum of Survival Motor Neuron Gene in Spinal Muscular Atrophy

Rad¹

2017

Down Syndr Chr Abnorm

View full text Add to dashboard Cite

Clinical Aspects of SMASpinal muscular atrophy (SMA), with an incidence of 1/10000 world-wide [1,2] is a lower motor neuron disease and characterized by symmetrical muscle weakness and atrophy resulting from progressive degeneration of alpha motor neurons and loss of the anterior horn cells in the spinal cord and the brain stem nuclei. The inheritance pattern of SMA is autosomal recessive and classified clinically into the following types, based on the age at onset and clinical severity: SMA 0 (prenatal onset), SMA I (Werdnig-Hoffmann disease with onset before age 6 months), SMA II (Dubowitz disease with onset between age 6 and 18 months), SMA III (Kugelberg-Welander disease with onset after age 18 months), and SMA IV (onset after age 18 years). After unraveling the genetic basis of SMA, all SMN1-associated clinical types can be considered as a continuum without a clear delineation. Survival Motor Neuron (SMN) GeneSurvival motor neuron (SMN) gene, the SMA determining gene, located on 5q12.2-q13.3 with two homologue copies, SMN1 (survival motor neuron 1; telomeric copy) and SMN2 (survival motor neuron 2; centromeric copy), which differ by only eight nucleotide (five are intronic and three are exonic, located within exons 6, 7, and 8) [3][4][5][6]. SMN1 and SMN2, both containing nine exons with 99% nucleotide identity, are arranged in tandem on each chromosome encoding a 294-amino acid RNA-binding protein. One of the coding sequence of SMN2 that differs from that of SMN1 by a single nucleotide (840 C>T) results in alternative splicing of exon 7 [4]. Due to the alternative splicing of exon 7, SMN2 genes produce a reduced amount of full length transcripts, and a variable amount of mRNA lacking exon 7, which give raise to a truncated and unstable protein [7], whereas SMN1 produces full-length transcripts.Full-length product of SMN1 is necessary for lower motor neuron function and loss of SMN1 is essential to the pathogenesis of SMA, while SMN2 copy number modifies the severity of phenotype. Copy Number Variation of SMN2 GeneThe number of SMN2 copies (arranged in tandem in cis configuration on each chromosome) ranges from zero to five that can be detected using quantitative PCR and MLPA methods [8,9]. The presence of three or more copies of SMN2 is associated with a milder phenotype [10][11][12][13]. All SMA patients retain at least one copy of SMN2, so, SMA is caused by low levels of SMN protein rather than complete absence of the protein. Most SMA type I patients have two copies of SMN2, three SMN2 copies are common in SMA type II, while type III and IV generally have three or four copies. On the other hand, no correlation exists between the loss of SMN1 exon 7 and the severity of disease, that is, the homozygous exon 7 deletions is observed with the same frequency in all phenotypes. Mutation Spectrum of SMN1 GeneApproximately 95%-98% of all types of SMA patients show homozygous deletion of SMN1 exon 7 (and exon 8 in the majority of cases) [14][15][16]. Approximately 6% of parents of a child with homozygous SMN1 del...

show abstract

A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA

Cited by 19 publications

References 20 publications

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

Genetic findings of Cypriot spinal muscular atrophy patients

Mutation Spectrum of Survival Motor Neuron Gene in Spinal Muscular Atrophy

Contact Info

Product

Resources

About