Family cancer histories predictive of a high risk of hereditary non‐polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1

Pj, Ainsworth; Koscinski, Daria; Fraser, BP; Stuart, JA

doi:10.1111/j.0009-9163.2004.00282.x

Cited by 12 publications

(8 citation statements)

References 8 publications

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“…In line with hundreds previous MLPA studies performed in various syndromes and diseases (Ainsworth et al, 2004;Madrigal et al, 2007;Priolo et al, 2008), we confirm that MLPA is an useful method to detect UBE3A exon deletions which otherwise would be missed using conventional gene-scanning methods. However, at the same time we need to claim about some limitations in the performance of MLPA for quantification analysis possibly leading to false positives as documented in our previous study (Calì et al, 2010).…”

Section: Resultssupporting

confidence: 89%

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

et al. 2010

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Abbreviations: AS, angelman syndrome; CMDA, comparative multiplex dosage analysis; MLPA, multiplex ligation-dependent probe amplification; RPA, relative peak area; UBE3A, ubiquitin protein ligase E3A AbstractAngelman syndrome (AS) is a severe neurobehavioural disorder caused by failure of expression of the maternal copy of the imprinted domain located on 15q11-q13. There are different mechanisms leading to AS: maternal microdeletion, uniparental disomy, defects in a putative imprinting centre, mutations of the E3 ubiquitin protein ligase (UBE3A) gene. However, some of suspected cases of AS are still scored negative to all the latter mutations. Recently, it has been shown that a proportion of negative cases bear large deletions overlapping one or more exons of the UBE3A gene. These deletions are difficult to detect by conventional gene-scanning methods due to the masking effect by the non-deleted allele. In this study, we have used for the first time multiplex ligation-dependent probe amplification (MLPA) and comparative multiplex dosage analysis (CMDA) to search for large deletions affecting the UBE3A gene. Using this approach, we identified a novel causative deletion involving exon 8 in an affected sibling. Based on our results, we propose the use of MLPA as a fast, accurate and inexpensive test to detect large deletions in the UBE3A gene in a small but significant percentage of AS patients.

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Section: Resultssupporting

confidence: 89%

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

et al. 2010

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“…In 1998, more relaxed criteria were introduced (Amsterdam II criteria [6]) to include cases of certain HNPCC-associated cancers other than colorectal cancer. A number of methods of identifying high-risk families have been proposed, with reference to both colorectal cancer and breast/ovarian cancer [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

SISE matters: the Sum of Information on Seventy-yr-old Equivalents measures pedigree information content when assessing the risk of HNPCC in a family

2005

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Hereditary non-polyposis colon cancer (HNPCC) is a significant cause of colorectal and other malignancies. Due to the lack of features that reliably differentiate between a sporadic case and an inherited case of colon cancer, it is likely that HNPCC is under reported. The diagnosis of HNPCC relies heavily on finding multiple cases of colorectal or other specific cancers within a family. In the absence of a significant family history, a diagnosis of HNPCC is seldom considered. We postulate that small kinships--or, more specifically, kinships with a low information content--are more likely to be designated as having a low risk of an inherited cancer predisposition than are large kinships. This has the potential to exacerbate the under-diagnosis of HNPCC in small families, leading to inadequate treatment, follow-up and family counselling. We have developed an objective measure of the information content of individual pedigrees called the Sum of Information on Seventy-yr-old Equivalents (SISE) coefficient. The SISE coefficient is a function of the number of relatives in a kinship and their relationship to the proband, of their ages and of the age-dependent penetrance of HNPCC mutations. A population-based series of colorectal cancer cases was assessed, by currently accepted methods, for the likelihood of there being an HNPCC mutation segregating in each family. We observed that families with a low SISE coefficient were significantly more likely to be designated at low risk of HNPCC (P< or =0.001). Using a cumulative binomial distribution function, we estimated the likelihood of observing multiple cancers in families of different SISE coefficients.

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“…The larger gDNA alterations create effective hemizygosity for single exons and result in an EBESA profile that is indistinguishable from homozygosity for two normal LDLR alleles. Multiplex ligation-dependent probe amplification (MLPA) is a new analytical method (11) that detects larger gDNA deletions or insertions that would otherwise be overlooked by EBESA (12). We hypothesized that some FH patients with no LDLR mutation detectable by EBESA would have an abnormality detectable using MLPA.…”

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confidence: 99%

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Wang

Ban

Hegele

2005

Journal of Lipid Research

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Autosomal dominant (AD) familial hypercholesterolemia [FH; Mendelian Inheritance in Man (MIM) 143890]typically results from mutations in the LDL receptor gene ( LDLR ), which are now commonly diagnosed using exon-byexon screening methods, such as exon-by-exon sequence analysis (EBESA) of genomic DNA (gDNA). However, many patients with FH have no LDLR mutation identified by this method. Part of the diagnostic gap is attributable to the genetic heterogeneity of AD FH, but another possible explanation is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR . Affected individuals have increased plasma LDL cholesterol, which without adequate diagnosis and intervention can increase the risk of fatal coronary heart disease by up to 100-fold compared with the general population (2).Fortunately, treatment with statin drugs can substantially reduce this risk and improve clinical outcome (2), stressing the importance of early and accurate diagnosis.At the molecular level, FH is now commonly diagnosed using exon-by-exon screening methods, such as exon-byexon sequence analysis (EBESA) of LDLR from genomic DNA (gDNA) (3, 4). However, this method finds mutations in only ‫ف‬ 50% of clinically diagnosed FH patents (3, 4). Part of the diagnostic gap is attributable to the heterogeneity of AD FH (5). For instance, HCHOLAD2 (MIM 144010), which results from a missense mutation in APOB affecting the LDL receptor binding domain of apolipoprotein B-100 (apoB-100; MIM 107730) (6, 7), accounts for 5-10% of the AD FH phenotype. A rare FH subtype called HCHOLAD3 (MIM 603776) results from mutations in PCSK9 (MIM 607786), encoding neural apoptosis-regulated convertase-1 (5, 8, 9). A similarly rare autosomal recessive FH subtype called HCHOLAR1 (MIM 603813) results from mutations in ARH (MIM 605747), encoding a putative adaptor for the LDL receptor (10). However, even after accounting for genetic heterogeneity, many clinically diagnosed FH patients have no LDLR mutation with EBESA.Another possible explanation for the gap in FH molecular diagnosis is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions. The larger gDNA alterations create effective hemizygosity for single exons and result in an EBESA profile that is indistinguishable from homozygosity for two normal LDLR alleles. Multiplex ligation-dependent probe amplification (MLPA) is a new analytical method (11) that detects larger gDNA deletions or insertions that would otherwise be overlooked by EBESA (12). We hypothesized that some FH patients with no LDLR mutation detectable by EBESA would have an abnormality detectable using MLPA. Of 70 unrelated FH patients, 44 had LDLR mutations detected by EBESA, including missense, RNA splic-

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Family cancer histories predictive of a high risk of hereditary non‐polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1

Cited by 12 publications

References 8 publications

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

SISE matters: the Sum of Information on Seventy-yr-old Equivalents measures pedigree information content when assessing the risk of HNPCC in a family

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

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