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S N Thibodeau

Publications and source records attributed to S N Thibodeau.

At least 109 records · Page 6Linked to original sources
PubMed1994

Reliability of diagnostic assessment of normal and premutation status in the fragile X syndrome using DNA testing.

Until recently, fragile X [fra(X)] syndrome was diagnosed by cytogenetic techniques and/or linkage analysis. Investigation of the mutation at the molecular level has shown that amplification of a polymorphic trinucleotide repeat (CGG) is diagnostic of this syndrome. Fu et al. [1991] observed that between 6-54 copies of the repeat were associated with alleles found in the general population, whereas 50-200 copies were associated with the premutation. In general, differences in copy number between the normal and premutated states are sufficiently large so that the probability of misclassification is, for all practical purposes, zero. However, there is a grey area in which members from both populations overlap. The purpose of our study was to determine the probability of misclassifying an individual from either the general or premutation population. DNA obtained from the general population and transmitting fra(X) females were analyzed from 3 centers in North America: Houston, Texas; Rochester, Minnesota; and Kingston, Ontario. The distribution of normal alleles from Houston was not significantly different from those obtained from Rochester. Therefore, these 2 samples were combined and the pooled distribution of normal alleles was compared with the pooled distribution of premutations. Results indicated that if 50 repeats were used as the cutoff criterion, sensitivity is 100%, specificity is 99.6%, and the probability that an individual has the fra(X) premutation given that the number of repeats is greater than 50 is 95%. Other cutoff criteria (45, 55, 60, 65) employed produced like findings, although 55 repeats appears to be a marginally superior criterion to 50. An independent sample from Kingston was used to verify the original assessments.(ABSTRACT TRUNCATED AT 250 WORDS)

Bayes Theorem↗
PubMed1994

Screening the dystrophin gene suggests a high rate of polymorphism in general but no exonic deletions in schizophrenics.

The dystrophin gene, located at chromosome Xp21, was evaluated as a candidate gene in chronic schizophrenia in response to the report of a large family in which schizophrenia cosegregated with Becker muscular dystrophy [Zatz et al., 1991: Am J Hum Genet 49: A364; 1992: J Med Genet 30(2):131-134]. Genomic DNA from 94 men with chronic schizophrenia was evaluated by Southern blot analysis using cDNA probes that span exons 1-59. No exonic deletions were identified. An unexpectedly high rate of polymorphism was calculated in this study and two novel polymorphisms were found, demonstrating the usefulness of the candidate gene approach even when results of the original study are negative.

Adult↗
PubMed1994

Microsatellite instability in Muir-Torre syndrome.

Muir-Torre syndrome (MTS) is characterized by the presence of at least one sebaceous tumor and at least one visceral malignancy. Although a wide range of internal malignancies have been reported, the most frequently observed internal neoplasm is colorectal carcinoma. MTS and hereditary nonpolyposis colorectal carcinoma (HNPCC) share many clinical and pathological characteristics and thus may share similar genetic mechanisms of tumorigenesis. Recently, microsatellite instability (MIN) has been reported in tumor tissue from patients with HNPCC. In order to determine if tumors from MTS patients might also show MIN, we examined DNA extracted from paraffin-embedded tissues for the presence of MIN at (CA)n repeats on chromosomes 5q, 15q, 17p, and 18q. Data was obtained on 13 patients, 9 of which had at least one colorectal tumor. Of these, six demonstrated widespread MIN in all sebaceous and colorectal tumors examined, as well as in a transitional cell carcinoma of the renal pelvis, a prostatic adenocarcinoma and a keratoacanthoma. Overall, patients with MIN differed from patients without MIN in several respects, the most important of which include: (a) uniform presence and early onset of colorectal cancer (average age, 40 versus 70 years); (b) prolonged survival following diagnosis of visceral malignancy (median survival, 32 versus 11 years); and (c) a greater number of visceral and skin tumors. These data suggests that patients with MTS may be composed of at least two subgroups, each demonstrating different genetic, pathological and clinical features. Furthermore, the subgroup demonstrating MIN may share similar genetic mechanisms of tumorigenesis with patients having HNPCC, supporting the notion that these syndromes are allelic.

Adult↗
PubMed1994

Circulating heart autoantibodies in familial as compared with nonfamilial idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is a serious heart disease characterized by enlargement of one or both ventricles and ventricular dysfunction. Although most patients have sporadic disease, 20% have been found to have familial DCM when relatives are investigated by echocardiography. No other factors have been identified to date that consistently distinguish familial from nonfamilial DCM. Although some patients have a family history of DCM, a "negative" family history does not exclude familial DCM because affected family members may be presymptomatic or undiagnosed. Because some patients have life-threatening complications at the time of initial assessment of DCM, identifying a serum marker predictive of familial disease would help determine which families would most likely benefit from echocardiographic investigation. OBJECTIVE: In this study, our objective was to determine whether antiheart autoantibodies could be used to distinguish familial from nonfamilial idiopathic DCM. METHODS: We analyzed serum specimens for antiheart antibodies from 19 patients categorized as having familial DCM and 15 classified as having nonfamilial DCM on the basis of echocardiographic investigation of first-degree relatives. The mean duration of disease in these 34 patients was 50 months at the time the serum specimens were obtained. RESULTS: Titers of antibodies against the adenine nucleotide translocator, branched-chain keto acid dehydrogenase, and cardiac myosin did not distinguish between familial and nonfamilial cases of DCM.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1994

Length of uninterrupted CGG repeats determines instability in the FMR1 gene.

Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3' end. Variation in the length of the repeat appears polar. Alleles containing between 34 and 55 repeats, with documented unstable transmissions, were shown to have lost one or both AGG interruptions. These comparisons define an instability threshold of 34-38 uninterrupted CGG repeats. Analysis of premutation alleles in Fragile X syndrome carriers reveals that 70% of these alleles contain a single AGG interruption. These data suggest that the loss of an AGG is an important mutational event in the generation of unstable alleles predisposed to the Fragile X syndrome.

Base Sequence↗
PubMed1994

Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation.

This study addresses mechanism of instability of the FMR-1 (CGG)n-repeat, and investigates features which may distinguish between normal stable and fragile X unstable repeats. To achieve this, we have sequenced 178 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n-repeat at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. We predict that certain sequence configurations [no AGG, and (CGG)9-11AGG(CGG) > or = 20] present in the general population, are predisposed towards replication slippage. Association between these proposed predisposing repeats and DXS548 alleles may explain the previously reported frequencies of fragile X mutations and large-size normal repeats on specific haplotype backgrounds. We propose that predisposing alleles arise in the general population by as yet undefined mechanism(s) which introduce a relatively long stretch of pure CGG repeat at the 3'-end (relative to the direction of transcription) of the FMR-1 repeat region. The 3' pure repeat may then be susceptible to further expansion by replication slippage. Slippage on these predisposing chromosomes could accumulate over many generations until a threshold size is reached, at which point the repeat is susceptible to greater instability (i.e. premutation stage). Thus, results suggest that evolution of fragile X full mutations could involve 4 definable stages: 1) ancestral events leading to the formation of predisposing alleles which have large total repeat length (e.g. between 35 to 50) but no AGG or 1 AGG; 2) gradual slippage of these predisposing alleles to small premutations (S alleles); 3) conversion from S alleles to larger premutations (Z); 4) massive expansion from a Z allele to a full mutation (L).

Alleles↗
PubMed1994

Identification of multiple endocrine neoplasia, type 2 gene carriers using linkage analysis and analysis of the RET proto-oncogene.

Ten kindreds (95 individuals) with multiple endocrine neoplasia, type 2 (MEN 2) were analyzed by linkage analysis using four highly polymorphic (CA)n-repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1). Additionally, we examined the RET proto-oncogene for specific mutations by DNA sequence analyses in these 10 plus 14 members of 3 additional kindred. Nine families had MEN 2A, two had MEN 2B, and two had medullary thyroid cancer alone (FMTC). Using these four markers, all 10 kindreds were informative, with 10 individuals predicted to be presymptomatic MEN 2 gene carriers and 23 individuals predicted not to be carriers. DNA sequence analysis of exons 10 and 11 of the RET proto-oncogene revealed a mutation in all nine MEN 2A kindreds. A missense mutation was found in each case, leading to a loss of a cysteine residue (codon 618 of exon 10 or codon 634 of exon 11). In the MEN 2A families, the linkage analysis and RET mutation analysis gave concordant results for prediction of gene carriers in 100% of the individuals tested. No mutations were found in the two kindreds with FMTC or the two MEN 2B kindreds. Two individuals from two different MEN 2A kindreds were identified who had abnormal calcitonin stimulation tests but were not MEN 2A gene carriers by both linkage analysis and RET mutation analysis. These individuals presumably represented the sporadic occurrence of abnormal calcitonin stimulation tests in the general population. These studies provide further support for a role of the RET proto-oncogene in the pathogenesis of MEN 2A. Additionally, in the absence of identifiable RET proto-oncogene mutations, linkage analysis using (CA)n-repeat markers is a highly accurate alternative for the identification of MEN 2 or FMTC gene carriers.

Drosophila Proteins↗
PubMed1994

Apolipoprotein E: risk factor for Alzheimer disease.

The apolipoprotein E gene (APOE) has three common alleles (epsilon 2, epsilon 3, and epsilon 4) that determine six genotypes in the general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-epsilon 4 allele. We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group. In the AD group, homozygosity for epsilon 4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-epsilon 4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.

Age of Onset↗
PubMed1993

Microsatellite instability in cancer of the proximal colon.

Colorectal tumor DNA was examined for somatic instability at (CA)n repeats on human chromosomes 5q, 15q, 17p, and 18q. Differences between tumor and normal DNA were detected in 25 of the 90 (28 percent) tumors examined. This instability appeared as either a substantial change in repeat length (often heterogeneous in nature) or a minor change (typically two base pairs). Microsatellite instability was significantly correlated with the tumor's location in the proximal colon (P = 0.003), with increased patient survival (P = 0.02), and, inversely, with loss of heterozygosity for chromosomes 5q, 17p, and 18q. These data suggest that some colorectal cancers may arise through a mechanism that does not necessarily involve loss of heterozygosity.

Adult↗
PubMed1993

Molecular-clinical correlations in children and adults with fragile X syndrome.

INTRODUCTION: Fragile X syndrome is the most commonly known inherited form of mental retardation. The intellectual abilities range from a normal IQ with learning disabilities to severe mental retardation. In males, there is a tendency for IQ decline in childhood. The purpose of this study was to correlate variations of the molecular cytosine guanine guanine (CGG) amplification in the fragile X mental retardation-1 (FMR-1) gene with the clinical findings, including IQ and physical features. METHODS: Full-scale IQ and cytogenetic results in 116 individuals with the FMR-1 mutation were studied. The IQ testing was performed with age-appropriate standardized tests. Physical features were summarized in a physical index score for each patient. The FMR-1 results were determined with the OX1.9 probe and the following system was used: P1 indicates premutation; P2, large premutation to small full mutation; P3, full mutation; and P4, mosaic. RESULTS/CONCLUSIONS: The findings showed that those females with a small insert in the P1 range had a significantly higher IQ than other heterozygotes (P2, P3, and P4 categories). P4 males had a significantly higher IQ than P2 or P3 males. In cross-sectional age comparisons, the slope of the IQ decline was greater in P2 males than in P4 or P3 males.

Adolescent↗
PubMed1993

The application of fluorescent in situ hybridization to detect Mbcr/abl fusion in variant Ph chromosomes in CML and ALL.

We investigated the usefulness of fluorescent in situ hybridization with different-colored major breakpoint cluster region (Mbcr) and Abelson oncogene (abl) probes in clinical practice. In standard Ph chromosomes with a Mbcr breakpoint, these probes produced a fusion of Mbcr and abl signals that was visible in interphase and metaphase cells. The normal range for apparent Mbcr/abl fusion signals in interphase nuclei was established in bone marrow from 25 normal controls. We tested the probes on 35 bone marrow specimens from five normal subjects and 29 patients with various kinds of Ph chromosomes and chronic myelogenous leukemia or acute lymphocytic leukemia. This method produced Mbcr/abl fusion signals in patients with a standard Ph chromosome, simple or complex variants of Ph chromosomes, and "Ph-negative chronic myelogenous leukemia." In metaphase cells of patients with acute lymphocytic leukemia, this method established Ph chromosomes with minor bcr (mbcr) breakpoints. Fluorescent in situ hybridization is a relatively inexpensive and rapid method. When this method is used in conjunction with conventional chromosome analysis, the cytogeneticist can combine the power of complete karyotype studies and the resolution of molecular techniques for patients suspected of having a Ph chromosome.

Bone Marrow Cells↗
PubMed1993

Autosomal dominant supravalvular aortic stenosis: localization to chromosome 7.

Supravalvular aortic stenosis (SVAS) is a localized or diffuse congenital narrowing of the ascending aorta which may occur sporadically, as a familial defect, or in association with Williams syndrome. Familial cases suggest an autosomal dominant gene defect but the underlying molecular basis of SVAS is unknown. In this study, we sought to localize the genetic defect in familial SVAS by linkage analysis in a large three generation family. A total of 44 polymorphic markers were examined for linkage, including 17 Southern blot-based RFLPs, 2 PCR-based RFLPs, and 25 microsatellites, primarily of the (CA)n repeat type. We report linkage of the disease phenotype to a highly informative (CA)n repeat marker, Mfd 50, at locus D7S440 which has been localized to chromosome arm 7q. Using a 100% penetrance model, which was more conservative than lower values of penetrance, a peak LOD score of 4.66 at a recombination frequency of 0.043 was found. A number of candidate genes have been localized to this region, including collagen 1A2, laminin B1, and elastin. Based on our preliminary linkage data, the abnormal microscopic appearance of aortic elastic fibers in SVAS, and analogous animal and human diseases associated with elastic fiber and vascular abnormalities, there is indirect evidence suggesting elastin as a possible candidate gene for this disorder.

Aortic Valve Stenosis↗
PubMed1993

Mosaic trisomy 16 in a thriving infant: maternal heterodisomy for chromosome 16.

Trisomy 16 is the most common trisomy in spontaneous abortions and is usually, if not always, lethal in the nonmosaic state. We report a liveborn infant with trisomy 16 mosaicism first diagnosed by amniocentesis at 20 weeks gestation. At birth, the infant was growth retarded and mildly dysmorphic. At age 14 months she was developmentally normal and had facial asymmetry. Her length, weight and head circumference were normal. Pure trisomy 16 was found in cells from the placenta. A normal female karyotype was found in lymphocytes from the infant. Skin fibroblasts revealed a trisomy 16 karyotype in 6 of 30 cells. Molecular analysis showed maternal uniparental heterodisomy, indicating that the trisomic conceptus arose from a nondisjunction of maternal meiosis. Fibroblasts may be the tissue of choice for detection of low-level trisomy 16 mosaicism.

Amniocentesis↗
PubMed1993

Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population.

In this study, we have characterized a CGG repeat at the FMR-1 locus in more than 100 families (more than 500 individuals) presenting for fragile X testing and in 247 individuals from the general population. Both Southern blot and PCR-based assays were evaluated for their ability to detect premutations, full mutations, and variability in normal allele sizes. Among the Southern blot assays, the probes Ox1.9 or StB12.3 with a double restriction-enzyme digest were the most sensitive in detecting both small and large amplifications and, in addition, provided information on methylation of an adjacent CpG island. In the PCR-based assays, analysis of PCR products on denaturing DNA sequencing gels allowed the most accurate determination of CGG repeat number up to approximately 130 repeats. A combination of a Southern blot assay with a double digest and the PCR-sequencing-gel assay detected the spectrum of amplification-type mutations at the FMR-1 locus. In the patient population, a CGG repeat of 51 was the largest to be stably inherited, and a repeat of 57 was the smallest size of premutation to be unstably inherited. When premutations were transmitted by females, the size of repeat correlated with risk of expansion to a full mutation in the next generation. Full mutations (large repeats typically associated with an abnormal methylation pattern and mitotic instability) were associated with clinical and cytogenetic manifestations in males but not necessarily in females. In the control population, the CGG repeat ranged from 13 to 61, but 94% of alleles had fewer than 40 repeats. The most frequent allele (34%) was a repeat of 30. One female had an allele (61 repeats) within a range consistent with fragile X premutations, while two other individuals each had a repeat of 52. This suggests that the frequency of unstable alleles in the general population may be approximately 1%.

Blotting, Southern↗
PubMed1992

APC mutations occur early during colorectal tumorigenesis.

Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.

Adenoma↗