De Novo and Inherited Deletions of the 5q13 Region in Spinal Muscular Atrophies

Melki, Judith; Lefebvre, Suzie; Bürglen, Lydie; Burlet, Philippe; Clermont, Olivier; Millasseau, P; Reboullet, Sophie; Bénichou, Bernard; Zeviani, Massimo; Paslier, Denis Le; Cohen, Daniel; Weissenbach, Jean; Münnich, Arnold

doi:10.1126/science.7910982

Cited by 294 publications

(207 citation statements)

References 20 publications

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“…Because of the incidence of SMA (homozygous deletion of SMN1) in the Swedish population is around 1 in 12 000 live births, 15 the frequency of heterozygous SMN1 deletions in Sweden can be estimated to be around 1/55, similar to what has been reported in France. 16 The frequency of heterozygous SMN1 deletions found in the Swedish population in this study was in accordance with those reports, suggesting that our control population was representative of the Swedish population as a whole. These lack of association between ALS and SMN1 gene copy number is in contrast to results in French and Dutch cohorts in which abnormal copy numbers of SMN1 have been associated with an increased risk of ALS.…”

Section: Discussionsupporting

confidence: 93%

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

et al. 2012

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Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semiquantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.

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Section: Discussionsupporting

confidence: 93%

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

et al. 2012

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“…These events can cause mutations leading to genetic disease (1)(2)(3). Human chromosome 5 contains such an area at 5q13-14, where the abundance of low-copy repeats has been well documented (4)(5)(6)(7)(8)(9). Interestingly, the gene for spinal muscular atrophy (SMA) has been mapped in tight linkage to this region (10,11).…”

mentioning

confidence: 99%

Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

Selig

Bruno

Scharf

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Low-copy repeats have been associated with genomic rearrangements and have been implicated in the generation of mutations in several diseases. Here we characterize a subset of low-copy repeats in the spinal muscular atrophy (SMA) region in human chromosome 5q13. We show that this repeated sequence, named c41-cad, is a highly expressed pseudogene derived from an intact neuronal cadherin gene, Br-cadherin, situated on Spl3-14. Br-cadherin is expressed specifically in the brain, whereas the c41-cad transcripts are 10-15 times more abundant and are present in all tissues examined. We speculate that the c41-cad repeats, separately or in concert with other repeats in the SMA region, are involved in the pathogenesis of SMA by promoting rearrangements and deletions.

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“…12,[33][34][35] In contrast, we detected a de novo mutation event by contrasting phased-SNP haplotypes to SMN1 dosages determined by qPCR and examining the segregation pattern of the haplotype and mutation in additional close relatives. The segregation of the haplotype and SMN1 deletion in this family indicated that the event occurred during a paternal meiosis, as in most other de novo SMN1 deletions.…”

Section: Discussionmentioning

confidence: 99%

A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

et al. 2011

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Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as B1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for B1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity.

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De Novo and Inherited Deletions of the 5q13 Region in Spinal Muscular Atrophies

Cited by 294 publications

References 20 publications

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

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