Genotype–phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina
Sofía MedranoSoledad MongesLuis Pablo GravinaLaura AlíasJ. MozzoniHilda Verónica AráozSara BernalAngélica MorescoLilien ChertkoffEduardo F. Tizzano
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Abstract Spinal muscular atrophy (SMA) is an autosomal recessive disorder associated with homozygous deletion of the survival motor neuron 1 gene ( SMN1 ). Its centromeric copy gene, SMN2 , is the major modifying factor. However, the genotype–phenotype correlation is incomplete and is therefore not useful in clinical practice. We studied a cohort of 103 patients in order to refine this correlation. In addition to standard disease severity data, we collected three additional criteria: age at death; brainstem involvement; and loss of ambulation. Gene dosage analysis was conducted by multiplex ligation‐dependent probe amplification (MLPA). SMN2 copynumber was highly correlated with survival duration in SMA type I and ambulation conservation or loss in type III. Among SMA severity groups, it was not significantly different in cases with brainstem involvement. Although the SMN2 copynumber could provide prognostic indications, clinical discrepancies still exist among patients, suggesting the existence of unidentified modifying factors. Muscle Nerve, 2011
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Objective To investigate the effect of multiplex ligation-dependent probe amplification (MLPA)in molecular diagnosis of spinal muscular atrophy(SMA).Methods Peripheral blood samples were collected from 13 SMA patients.31 parents of SMA patients,50 healthy individuals without family history of SMA,and 10 specimens of amniotic fluid from these families were collected too.Genomic DNA was analyzed by MLPA,conventional PCR-RFLP,and allele-specific PCR.Results In complete agreement with the results of conventional PCR-RFLP and allele-specific PCR.MLPA analysis showed that all of the 13 patients had homozygous deletion of the Survival of motor neuron 1(SMN1)geBe,and there Wag significant difference between the SMA severity(type I to typeⅢ)and SMN2 copy humber(P<0.05).of the 31 parents 29(93.5%)had 1 copy of SMNI,2(6.5%)had 2 copies of SMN1.Of the 50 healthy individuals.1(2.0%)had 1 copy of SMN1,48(96.O%)had 2 copies of SMN1,and 1(2.0%)had 3 copies.The SMN1 copy humber of the parents was significantly higher than that of the healthy individuals (P<0.01).Two of the 10 feruses had homozygous deletion of SMN1.Conclusion The MLPA technique has proved to be an accurate and reliable tool for the molecular diagnosis of SMA.both in patients and in healthy carriers.
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Muscular disorders,atrophy; Diagnosis; Multiplex ligation-dependent probe amplification; Survival motor neuron gene
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Objective To carry out prenatal diagnosis for families with high risk for spinal muscular atrophy (SMA) by using multiplex ligation-dependent probe amplification (MLPA). Methods Twenty-one families were enrolled. MLPA was used to detect copy numbers of SMN1 and SMN2 genes. Maternal contamination was excluded by using a short tandem repeat method. Results For 23 fetuses from the 21 families, 14 were identified as carriers, 1 as SMA patient, and 8 as normal. By linkage analysis of parental samples, three individuals were determined as silent (2+0) carriers. Conclusion MLPA can determine the carrier status of SMA. The identification of three silent (2+0) carriers among the 44 parental samples indicated a risk for such families, for which genetic counseling and reproduction guidance should be provided.
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Objectives To study the application of multiplex ligation-dependent probe amplification(MLPA) in molecular diagnosis of spinal muscular atrophy(SMA) as basis for SMA genetic counseling.Methods Peripheral blood samples were collected from three SMA suspected patients and their parents.Genomic DNA was isolated and analyzed by MLPA.Results MLPA analysis showed that all the 3 children had homozygous deletion of the survival of motor neuron l(SMN1) gene and the copy number was 0.Both of the parents had heterozygous deletion of the SMN1 gene and the copy number was 1.Conclusions Application of MLPA in molecular diagnosis of SMA not only makes diagnosis quick and easy,but also identifies and screens the gene heterozygous deletion of carriers.
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To describe the occurrence of spinal muscular atrophy (SMA) in childhood; to evaluate if any of the genes in the SMA region on chromosome 5q13 correlates with disease severity; to make genotype-phenotype correlations; to evaluate the variability of different disease alleles in carriers and the sensitivity of multiplex ligation-dependent probe amplification (MLPA) for detecting carriers.In a population-based study from Western Sweden MLPA was used to determine the copy-numbers of several genes in the SMA region (SMN1, SMN2, BIRC1, GTF2H2 and SERF1A) in SMA-patients and their parents.We estimated the incidence of SMN1-related SMA in childhood at 1 in 11 800 live births and confirmed the relationship between the number of SMN2 copies and the severity of disease. No other direct relationships were found. All but one of the analysed parents were confirmed as carriers by MLPA analysis. A total of at least 30 different disease alleles were identified and no specific disease allele represented more than 15% of the total.The childhood incidence of SMA in the Swedish population is around 1 in 12,000 live births and it is unlikely that there is any founder effect involved in SMA in western Sweden.
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To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients.A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University's Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers.Using PCR-RFLP test, 159 of 324 postnatal and 18 of 77 prenatal cases were detected to have SMN1 deletions. From positive samples, 88.13% had a homozygous deletion in both exon 7 and exon 8 of SMN1. Using MLPA, 54.5% of families revealed heterozygous deletions of SMN1, and 2 or 3 copies of SMN2, suggesting a healthy SMA carrier. Among patients referred for SMA testing, the annual percentage of patients diagnosed as SMA has decreased gradually from 90.62% (2003) down to 20.83% (2014).Although PCR-RFLP method is a reliable test for SMA screening, MLPA is a necessary additional test and provide relevant data for genetic counseling of families having previously affected child. The gradual decrease in the percentage of patients molecularly diagnosed as SMA shows that clinicians have begun to use genetic tests in the differential diagnosis of muscular atrophies. Cost and availability of these genetic tests has greatly attributed to their use.
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