Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome

Mailman, Matthew D.; Hemingway, Tamara; Darsey, Rebecca L.; Glasure, Carol E.; Huang, Ying; Chadwick, Robert B.; Heinz, John W.; Papp, Audrey C.; Snyder, Pamela J.; Sedra, Mary S.; Schafer, Robert W.; Abuelo, Dianne; Reich, Elsa; Theil, Karl S.; Burghes, Arthur H.M.; Chapelle, Albert de la; Prior, Thomas W.

doi:10.1007/s004390000446

Cited by 40 publications

(29 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Monosomal hybrid generation, which would separate the two chromosome 5s, could enable distinction between '2 þ 0' and '1 þ 1' genotypes. 23 However, this type of analysis is not practical in a diagnostic laboratory and linkage analysis still remains the most achievable option.…”

Section: Genotypes In Sma Carriersmentioning

confidence: 99%

Population screening and cascade testing for carriers of SMA

et al. 2007

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is one of the most common autosomal-recessive diseases, caused by absence of both copies of the survival motor neuron 1 (SMN1) gene. Identification of SMA carriers has important implications for individuals with a family history and the general population. SMA carriers are completely healthy and most are unaware of their carrier status until they have an affected child. A total of 422 individuals have been studied to identify SMA carriers. This cohort included 117 parents of children homozygously deleted for SMN1 (94% were carriers and 6% had two copies of SMN1; of these individuals, two in seven had the '2 þ 0' genotype, two in seven were normal but had children carrying a de novo deletion and three in seven were unresolved), 158 individuals with a significant family history of SMA (47% had one copy, 49% had two copies and 4% had three copies of SMN1) and 146 individuals with no family history of SMA (90% had two copies, 2% had one copy and 8% had three copies of SMN1). The SMA carrier frequency in the Australian population appears to be 1/49 and the frequency of two-copy SMN1 alleles and de novo deletion mutations are both at least 1.7%. A multimodal approach involving quantitative analysis, linkage analysis and genetic risk assessment (GRA), facilitates the resolution of SMA carrier status in individuals with a family history as well as individuals of the general population, providing couples with better choices in their family planning.

show abstract

Section: Genotypes In Sma Carriersmentioning

confidence: 99%

Population screening and cascade testing for carriers of SMA

et al. 2007

View full text Add to dashboard Cite

show abstract

“…10,11 Some genotype/phenotype correlations have been established among patients who carry SMN1 point mutations, and in general, the presence of additional copies of SMN2 positively modifies clinical prognosis. 12,13 The majority of mutations causing all SMA subtypes involve SMN1 copy-number loss. Consequently, carrier screening must be performed by dosage-sensitive methods that can distinguish SMN1 from SMN2, including quantitative PCR, 14 multiplex ligation-dependent probe amplification (MLPA), 15 and/or TaqMan quantitative technology.…”

Section: Introductionmentioning

confidence: 99%

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

Luo

Liu

Peter

et al. 2014

Genetics in Medicine

View full text Add to dashboard Cite

“…11 Importantly, SMA carriers may have two copies of SMN1 on one chromosome 5 and a deletion/conversion mutation of SMN1 on the other chromosome 5 (the '2 þ 0' SMN1 genotype). 10 By dosage analysis alone, such carriers, as well as carriers of small, intragenic mutations, are indistinguishable from normal individuals with one copy of SMN1 on each chromosome 5, unless a monosomal analysis technique 12 is utilized. Adding to the complexity of SMA genetics is a high de novo SMN1 mutation rate.…”

Section: Introductionmentioning

confidence: 99%

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

2004

View full text Add to dashboard Cite

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.

show abstract

Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome

Cited by 40 publications

References 46 publications

Population screening and cascade testing for carriers of SMA

Population screening and cascade testing for carriers of SMA

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

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

Contact Info

Product

Resources

About