Spinal Muscular Atrophy Genetic Testing Experience at an Academic Medical Center

Ogino, Shuji; Leonard, Debra G.B.; Rennert, Hanna; Wilson, Robert B.

doi:10.1016/s1525-1578(10)60680-0

Cited by 39 publications

(43 citation statements)

References 28 publications

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“…9 Subsequently, by molecular analysis, a more reduced rate of SMA-affected pregnancies was noted, although these reports included couples without proven carrier status. 10,11 A recent paper 7 describes a TRD of the SMN1 allele based on the molecular analysis of 314 prenatal tests. These authors found a statistically significant deviation in favour of the wild-type allele (344 vs 284 P ¼ 0.016) with a decrease in the number of affected foetuses (20.7%).…”

Section: Discussionmentioning

confidence: 99%

Evidence of a segregation ratio distortion of SMN1 alleles in spinal muscular atrophy

et al. 2007

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Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterised by degeneration and loss of the motor neurons of the anterior horn of the spinal cord. The absence of SMN1 is determinant to have SMA and parents of SMA patients are regarded as carriers of the disease. We compared the segregation ratio of the mutated allele and the wild-type allele of all the confirmed carrier parents assuming Mendelian proportions. Results of transmissions in 235 prenatal tests and in 128 unaffected siblings showed a statistically significant deviation in favour of the wild-type SMN1 allele. The number of affected foetuses and carriers were lower than that expected. No significant differences in the sex ratio or in the progenitor origin of the transmitted allele to the carriers were found. One hypothesis that has been advanced to account for the distortion observed in affected foetuses is the negative postzygote selection due to early miscarriage. However, given that the number of carriers in our series was lower than expected, prezygote events such as meiotic drive, survival of gametes or preferential fertilisation should also be considered.

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Section: Discussionmentioning

confidence: 99%

Evidence of a segregation ratio distortion of SMN1 alleles in spinal muscular atrophy

et al. 2007

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“…4,10 We meta-analyzed published data, 3,4,8,10,13,14 and updated deduced SMN1 allele frequencies 5 as follows: 'zero-copy allele' (chromosome 5 lacking SMN1 exon 7), 9.83 Â 10 À3 ; 'one-copy allele', 9.57 Â 10 À1 ; 'two-copy allele' (chromosome 5 with two copies of SMN1 exon 7), 3.27 Â 10 À2 ; and '1 D allele' (chromosome 5 with a small intragenic mutation in SMN1), 1.80 Â 10 À4 . One hypothesis to explain the presence of two copies of SMN1 on one chromosome 5 is unequal crossing over between homologous chromosomes during meiosis.…”

Section: Discussionmentioning

confidence: 99%

Inverse correlation between SMN1 and SMN2 copy numbers: evidence for gene conversion from SMN2 to SMN1

et al. 2003

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Most carriers of autosomal recessive spinal muscular atrophy (SMA) have only one copy of SMN1 because of SMN1 gene deletions or gene conversions from SMN1 to SMN2, which has only one base difference in coding sequence from SMN1. Using SMN gene dosage analysis, we determined the copy numbers of SMN1 and SMN2 in the general population as well as in SMA patients and carriers. Increased SMN1 copy number is associated with decreased SMN2 copy number in the general population; that is, SMN2 copy number was decreased to one or zero copies in 11 of 13 individuals with three or four copies of SMN1, whereas only 71 of 164 individuals with two copies of SMN1 had one or zero copies of SMN2 (Po0.01). SMN2 copy number was increased to three or four in a subset of SMN1 deletion/conversion carriers, and in most SMA patients with a milder phenotype. In conclusion, our data provide evidence that gene conversion from SMN2 to SMN1 occurs, and that SMN1 converted from SMN2 is present in the general population.

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“…These were new cases in addition to those analyzed for our previous studies. 11,18 Results were anonymized and used for this study. There was no evidence for the presence of any ethnic group with skewed SMN1 or SMN2 copy numbers.…”

Section: Methodsmentioning

confidence: 99%

“…We included the following data: the frequencies of individuals with one, two, three, and four copies of SMN1 in the general population 9,18,21 -24 (and this study) (Table 1); the fraction of individuals for each SMA type who lack both copies of SMN1 exon 7 among those with identifiable mutations in both SMN1 alleles; 25 and the frequency of patients completely lacking SMN1 who received a de novo SMN1 deletion/conversion mutation. 1,13,18,23,25 We excluded data from other studies for reasons described previously. 1 The data of Cusin et al 23 include those of Gerard et al 26 (V Cusin, personal communication).…”

Section: Methodsmentioning

confidence: 99%

New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations

2004

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Most spinal muscular atrophy patients lack both copies of SMN1. Loss of SMN1 ('0-copy alleles') can occur by gene deletion or SMN1-to-SMN2 gene conversion. Despite worldwide efforts to map the segmental duplications within the SMN region, most assemblies do not correctly delineate these genes. A near pericentromeric location provides impetus for the strong evidence that SMN1 and SMN2 arose from a primate-specific paralogous gene duplication. Here we meta-analyzed our recent laboratory results together with available published data, in order to calculate new mutation rates and allele/haplotype frequencies in this recalcitrant and highly unstable region of the human genome. Based on our tested assumption of compliance with Hardy -Weinberg equilibrium, we conclude that the SMN1 allele frequencies are: '0-copy disease alleles,' 0.013; '1-copy normal alleles,' 0.95; '2-copy normal alleles (ie, two copies of SMN1 on one chromosome),' 0.038; and '1 D disease alleles (SMN1 with a small intragenic mutation),' 0.00024. The SMN1 haplotype ['(SMN1 copy number)-(SMN2 copy number)'] frequencies are: '0-0,' 0.00048; '0-1,' 0.0086; '0-2,' 0.0042; '1-0,' 0.27; '1-1,' 0.66; '1-2,' 0.015; '2-0,' 0.027; and '2-1,' 0.012. Paternal and maternal de novo mutation rates are 2.1 Â 10 À4 and 4.2 Â 10 À5 , respectively. Our data provide the basis for the most accurate genetic risk calculations, as well as new insights on the evolution of the SMN region, with evidence that nucleotide position 840 (where a transition 840C4T functionally distinguishes SMN2 from SMN1) constitutes a mutation hotspot. Our data also suggest selection of the 1-1 haplotype and the presence of rare chromosomes with three copies of SMN1.

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Spinal Muscular Atrophy Genetic Testing Experience at an Academic Medical Center

Cited by 39 publications

References 28 publications

Evidence of a segregation ratio distortion of SMN1 alleles in spinal muscular atrophy

Evidence of a segregation ratio distortion of SMN1 alleles in spinal muscular atrophy

Inverse correlation between SMN1 and SMN2 copy numbers: evidence for gene conversion from SMN2 to SMN1

New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations

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