Genetic risk assessment in carrier testing for spinal muscular atrophy

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

doi:10.1002/ajmg.10425

Cited by 168 publications

(131 citation statements)

References 39 publications

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“…This confirmed the complex structural organization of the human SMN gene and is similar to previous observations in Caucasian, Korean, Australian, and African populations. 2,3,[13][14][15][16][17][18][19] Simultaneously, we compared SMN1 alleles and genotype frequencies among different races. There were no significant differences among Chinese, Caucasian, Korean, Australian, American, and African populations, which showed that there were no racial or regional differences with respect to SMA in general populations.…”

Section: Discussionmentioning

confidence: 99%

“…Using quantitative analysis of SMN1/SMN2 gene dosage, a range of molecular investigations of the incidence of carriers and the genetic burden of SMA in diverse ethnic populations have been carried out. 2,3,[13][14][15][16][17][18][19] However, a population-based study of SMA prevalence in mainland China has not yet been executed. Although some data have been reported for subjects from Taiwan and Hong Kong, the analyses included a relatively small number of SMA patients.…”

Section: Introductionmentioning

confidence: 99%

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Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

Sheng-Yuan

Xiong

Chen³

et al. 2010

Eur J Hum Genet

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Screening for carriers of spinal muscular atrophy (SMA) is necessary for effective clinical/prenatal diagnosis and genetic counseling. However, a population-based study of SMA prevalence in mainland China has not yet been conducted. In this study, the copy number of survival motor neuron (SMN) genes was determined in 1712 newborn cord blood samples collected from southern China and from 25 core families, which included 26 SMA patients and 44 parents, to identify SMA carriers. The results presented 13 groups with different SMN1/SMN2 ratios among 1712 newborn individuals, which corresponded to 1535 subjects with two copies of SMN1, 119 with three copies of SMN1, 17 with four copies of SMN1, and 41 with a heterozygous deletion of SMN1 exon 7. Simultaneously, two '2+0' genotypes and two point mutations were found among the 44 obligate carriers in the core families, including a novel SMN1 splice-site mutation that was identified in the junction between intron 6 and exon 7 (c. 835-1G4A). These results indicated that the carrier frequency is 1/42 in the general Chinese population and that duplicated SMN1 alleles and de novo deletion mutations are present in a small number of SMA carriers. In addition, we developed and validated a new alternative screening method using a reverse dot blot assay for rapid genotyping of deletional SMA. Our research elucidated the genetic load and SMN gene variants that are present in the Chinese population, and could serve as the basis for a nationwide program of genetic counseling and clinical/prenatal diagnosis to prevent SMA in China.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

Sheng-Yuan

Xiong

Chen³

et al. 2010

Eur J Hum Genet

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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%

“…We used results from all available individuals with no family history of SMA, (N=180) 10 and 107 parents of an SMA patient; either parents with only one copy of SMN1, or parents of an SMA child who lacked SMN1 or had only one copy of SMN1 with a high clinical index of suspicion for SMN1-related SMA. Results were anonymized and used for our study.…”

Section: Methodsmentioning

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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“…15 This is because the frequency of single-copy carriers in the general population (ϳ2%) approaches the frequency of individuals affected with SMN1-related SMA who have a single-copy test result (ϳ3.6% 12 ). 16 The copy number of SMN2 correlates inversely with disease severity. 9,10,[12][13][14] Feldkö tter et al 14 found that SMN2 copy number also correlates directly with length of survival.…”

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confidence: 99%

Quantification of PCR Bias Caused by a Single Nucleotide Polymorphism in SMN Gene Dosage Analysis

Ogino

Wilson

2002

The Journal of Molecular Diagnostics

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Approximately 94% of patients with spinal muscular atrophy lack both copies of SMN1 exon 7, and most carriers have only one copy of SMN1 exon 7. We described previously the effect of SMN1/SMN2 heteroduplex formation on SMN gene dosage analysis, which is a multiplex quantitative PCR assay to determine the copy numbers of SMN1 and SMN2 using DraI digestion to differentiate SMN2 from SMN1. We describe herein the quantification of PCR bias between SMN1 exon 7 and SMN2 exon 7, which differ by only one nucleotide that is not present in either primer binding site. Using samples from 272 individuals with various SMN genotypes, we found that the amplification efficiency of SMN2 was consistent only approximately 80% that of SMN1. Thus, even a single nucleotide polymorphism, not in primer binding sites, can cause reproducible PCR bias. The precision and accuracy of our SMN gene dosage analysis are high because our assay design and controls take advantage of the consistency of the PCR bias. As additional clinically significant single nucleotide polymorphisms (SNPs) are discovered, assessment of PCR bias, and judicious selection of standards and controls, will be increasingly important for quantitative PCR assays. Spinal muscular atrophy (SMA: type I, MIM no. 253300; type II, MIM no. 253550; type III, MIM no. 253400) is an autosomal recessive disorder associated with loss of motor neurons in the anterior horn of the spinal cord and caused by mutations in the Survival Motor Neuron 1 gene (SMN1; MIM no. 600354) on 5q13. 1 Coding regions of SMN1 and its centromeric homologue, SMN2 (MIM no. 601627), differ in only one base. 2 This C-to-T substitution in SMN2 exon 7 affects the activity of an exonic splice enhancer and alters the splicing pattern of SMN2 mRNA, 3 resulting in a lower level of full-length SMN transcript from SMN2 than from SMN1. 4 -6 SMN2 was shown to be unique to Homo sapiens. 7 Approximately 94% of clinically typical SMA patients lack both copies of SMN1 exon 7. 8 SMN gene dosage analysis, a method to determine the copy number of SMN1, can be used to identify SMA carriers. Exon 7 of SMN1 and SMN2 are co-amplified with genomic and internal standards. The PCR products are then digested with DraI, which cuts only SMN2 exon 7 PCR products, followed by quantification of the PCR products. 9 -11 Other methods for SMN gene dosage analysis have been described. 12-14 A single copy of SMN1 by gene dosage analysis confirms carrier status; this analysis is therefore of clinical importance. A single-copy result also supports the diagnosis of SMN1-related SMA in an affected individual, who may have one deleted allele and one allele with a small intragenic mutation. However, the final diagnosis depends largely on the index of clinical suspicion. 15 This is because the frequency of single-copy carriers in the general population (ϳ2%) approaches the frequency of individuals affected with SMN1-related SMA who have a single-copy test result (ϳ3.6% 12 ). 16 The copy number of SMN2 correlates inversely with disease severity. 9,10,[12]...

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Genetic risk assessment in carrier testing for spinal muscular atrophy

Cited by 168 publications

References 39 publications

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

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

Quantification of PCR Bias Caused by a Single Nucleotide Polymorphism in SMN Gene Dosage Analysis

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