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PubMed2007

Evidence for linkage of red blood cell size and count: genome-wide scans in the Framingham Heart Study.

Red blood cell (RBC) count and size are major criteria for evaluating anemia and related hematology disease diagnoses. While environmental factors influence RBC count (RBCC) and size, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), studies have indicated that each of these measures has a substantial genetic component. So far, no linkage analysis or genome scan has been reported. We carried out 10 cM genome-wide scans on RBCC, MCV, and MCH in a community-based Caucasian cohort, the Framingham Heart Study, using 325 pedigrees with 1,144 individuals genotyped and phenotyped. Using variance-component linkage methods, heritabilities were estimated as 56, 52, and 52% after covariate adjusted for RBCC, MCV, and MCH, respectively. For RBCC, we found a maximum LOD score of 3.2 on chromosome 19, 24 cM (7.0 Mbp). Near this region, there lie a few important candidate genes, including erythropoietin receptor and erythroid Krüppel-like factor. For linkage analyses for MCV and MCH, there were coinciding maximized LOD scores on chromosome 11, 9 cM (5.2 Mbp) with values of 3.8 and 3.6, respectively. Under the peak resides the hemoglobin beta cluster - several beta-like genes, which are important candidates for RBC size. In subsequent analyses, we excluded individuals with low MCV to assess the possible influence of beta-thalassemia carriers, and there continued to be evidence for linkage in the same region on chromosome 11p15 (LOD scores of 2.6 and 2.7 for MCV and MCH, respectively). For MCV, we also identified a new region on chromosome 6q24 with a LOD score of 2.9. These findings suggest that further studies are warranted to identify potential causal genetic variants for RBC size and count and related erythrocyte indices.

Adolescent↗
PubMed2006

Association analyses of CYP19 gene polymorphisms with height variation in a large sample of Caucasian nuclear families.

Human height is a complex trait regulated by multiple genetic and environmental factors. CYP19 (cytochrome P450 19) encodes aromatase, which catalyses the rate-limiting step in the conversion of androgens to estrogens. Deleterious mutations in CYP19 can result in estrogen deficiency that will influence adult height to certain extent. In the present study, we aimed to test the associations between the CYP19 gene polymorphisms with adult height variation, using family-based association methods, such as QTDT (quantitative transmission disequilibrium test) and FBAT (family-based association test) in 1,873 subjects from 405 Caucasian nuclear families. We found one SNP (rs730154) significantly associated with height by both QTDT (P=0.0030) and FBAT (P=0.0016) analyses. Haplotype analyses corroborated our single-marker results by showing that the haplotypes in block 4 containing rs730154 were significantly associated with height variation. We thus concluded that CYP19 could be one of the genetic factors influencing adult height in Caucasians. Further studies are required to identify the causal functional variants responsible for Caucasian height within the CYP19 gene.

Adult↗
PubMed2004

Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD.

Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained.

Attention Deficit Disorder with Hyperactivity↗
PubMed1997

Haplotypes of angiotensinogen in essential hypertension.

The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Cancasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)n alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)16 explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-6A polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.

Age of Onset↗
PubMed2003

Mapping quantitative trait loci affecting female reproductive traits on porcine chromosome 8.

An understanding of the genetic control of porcine female reproductive performance would offer the opportunity to utilize natural variation and improve selective breeding programs through marker-assisted selection. The Chinese Meishan is one of the most prolific pig breeds known, farrowing three to five more viable piglets per litter than the European Large White breed. This difference in prolificacy is attributed to the Meishan's superior prenatal survival levels. The present study utilized a three-generation cross in which the founder grandparental animals were purebred Meishan and Large White pigs in a scan for quantitative trait loci (QTL) on porcine chromosome 8 (SSC8) associated with reproductive performance. Reproductive traits, including number of corpora lutea (ovulation rate), teat number, litter size, and prenatal survival, were recorded for as many as 220 F2 females. Putative QTL for the related traits of litter size and prenatal survival were identified at the distal end of the long arm of SSC8. A physiological candidate gene, SPP1, was found to lie within the 95% confidence interval of these QTL. A suggestive QTL for teat number was revealed on the short arm of SSC8. The present study demonstrates, to our knowledge, the first independent confirmation of QTL for fecundity on SSC8, and these QTL regions provide a crucial starting point in the search for the causal genetic variants.

Algorithms↗
PubMed2005

Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease.

BACKGROUND AND AIMS: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions. PATIENTS AND METHODS: The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed. RESULTS: No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery. CONCLUSION: Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.

Adolescent↗
PubMed2004

Positional identification of hypertension susceptibility genes on chromosome 2.

Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (N=461; N=778) and whites (N=550; N=967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.

Chromosomes, Human, Pair 2↗
PubMed2006

Genomewide linkage scan for quantitative trait loci underlying variation in age at menarche.

CONTEXT: Age at menarche (AAM) is an important anthropological variable that has major implications for a woman's health later in life. Genetic influence has been shown to contribute greatly to AAM, but the specific genetic determinants are largely unknown. OBJECTIVE: The objective of this study was to identify the quantitative trait loci (QTL) underlying the variations in AAM. METHODS: We performed a large-scale, genomewide, linkage scan in 2461 Caucasian women from 402 pedigrees. All subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome. Using the variance component method, we conducted multipoint linkage analyses and two-locus tests for epistatic interaction. RESULTS: The strongest linkage signal was obtained at the genomic region of 22q13 (LOD, 3.70); the other two suggestive linkages were on 22q11 (LOD, 2.68) and 11q23 (LOD, 1.98), respectively. We also detected significant epistatic interaction between genomic regions 22q13 and 3q13. CONCLUSIONS: The identification of QTL and epistatic interaction in a large female sample laid a foundation for independent replication and fine-mapping studies as well as positional and functional candidate gene studies aimed at finding the causal genetic variants and hidden mechanisms concerning the variations in AAM.

Age Factors↗
PubMed2006

Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women.

CONTEXT: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1. OBJECTIVE: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women. DESIGN: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program. MAIN OUTCOME MEASURES: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298). RESULTS: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LS-BMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/+1245G) had increased BMD (P = 0.007 for LS-BMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype. CONCLUSIONS: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.

Absorptiometry, Photon↗
PubMed2005

Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis.

UNLABELLED: A genome-wide screen was conducted using a large white sample to identify QTLs for FNCS geometry. We found significant linkage of FNCS parameters to 20q12 and Xq25, plus significant epistatic interactions and sex-specific QTLs influencing FNCS geometry variation. INTRODUCTION: Bone geometry, a highly heritable trait, is a critical component of bone strength that significantly determines osteoporotic fracture risk. Specifically, femoral neck cross-sectional (FNCS) geometry is significantly associated with hip fracture risk as well as genetic factors. However, genetic research in this respect is still in its infancy. MATERIALS AND METHODS: To identify the underlying genomic regions influencing FNCS variables, we performed a remarkably large-scale whole genome linkage scan involving 3998 individuals from 434 pedigrees for four FNCS geometry parameters, namely buckling ratio (BR), cross-sectional area (CSA), cortical thickness (CT), and section modulus (Z). The major statistical approach adopted is the variance component method implemented in SOLAR. RESULTS: Significant linkage evidence (threshold LOD = 3.72 after correction for tests of multiple phenotypes) was found in the regions of 20q12 and Xq25 for CT (LOD = 4.28 and 3.90, respectively). We also identified eight suggestive linkage signals (threshold LOD = 2.31 after correction for multiple tests) for the respective geometry traits. The above findings were supported by principal component linkage analysis. Of them, 20q12 was of particular interest because it was linked to multiple FNCS geometry traits and significantly interacted with five other genomic loci to influence CSA variation. The effects of 20q12 on FNCS geometry were present in both male and female subgroups. Subgroup analysis also revealed the presence of sex-specific quantitative trait loci (QTLs) for FNCS traits in the regions such as 2p14, 3q26, 7q21 and 15q21. CONCLUSIONS: Our findings laid a foundation for further replication and fine-mapping studies as well as for positional and functional candidate gene studies, aiming at eventually finding the causal genetic variants and hidden mechanisms concerning FNCS geometry variation and the associated hip fractures.

Adult↗
PubMed2000

Genetic susceptibility to childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The origin of this disease can be explained by a combination of genetic susceptibility factors and environmental exposures. For the purpose of our study it can be considered as a complex disease, caused by the "carcinogenic" effect of the environment modified by a series of genes. In population, these genes tend to occur in allelic forms representing functional polymorphisms thus explaining inter-individual variability in cancer susceptibility. The latter can be evaluated more realistically in childhood ALL than in sporadic cancers of the adult because of its relatively short latency period. We asked therefore, the question about the role of genes controlling the efficiency of xenobiotics metabolism in childhood leukemogenesis. Xenobiotics (drugs and carcinogens) are excreted from the body after metabolic conversion by enzymes mediating oxidation activation (Phase I) and conjugation detoxificaton (Phase II). Functional variants of these enzymes, resulting from known DNA polymorphisms in the corresponding genes, were shown to influence the risk to a variety of solid tumours in adults. A case-control study on ALL patients and healthy controls in a French-Canadian population was carried out by examining the loci of Phase I, CYP1A1 and CYP2D6, as well as Phase II enzymes, GSTM1, GSTT1, NAT1 and NAT2. The NAT2 slow-acetylator, CYP1A1*2A and GSTM1 null genotypes were shown to be significant risk determinants of ALL (OR=1.6, 1.8 and 1.8, respectively), whereas, polymorphisms in CYP2D6 and GSTT1 genes did not seem to play an important role in the aetiology of ALL. Interestingly, the risk associated with NAT2 slow-acetylators was most apparent among males homozygous for NAT1*4 (OR=3.3) whereas girls carrying the CYP1A1*4 allele were significantly underrepresented in the patient group (OR=0.2). These findings point to a gender-specific effect of DNA variants which, at least in part, may explain why ALL is more prevalent among boys. To assess gene-gene interactions, NAT2 slow-acetylators were considered together with GSTM1 null genotypes and CYP1A1*2A alleles. The combined presence of two risk-elevating genotypes appeared to confer an increased risk of ALL among the carriers (OR=2.6). This risk was increased further (OR=3.3) when all three genotypes occurred in the same individuals indicating that the combination of susceptibility variants is more predictive of risk then either of them independently. The association of leukemogenesis in children with metabolising gene variants suggests causal relation to environmental exposures.

Adult↗
PubMed1976

[Complete alpha-1-antitrypsin deficiency in a patient with Ehlers-Danlos syndrome].

Complete alpha-1-antitrypsin deficiency of the type PiOO associated with chronic obstructive lung disease, cutaneous hyperextensibility and hyperlaxity of joints were found in a nineteen-year-old Moroccan boy. On a nosological point of view, this patient could be included as a 8th form, in the Ehlers-Danlos syndrome which now groups seven clinical variants. A causal relationship between the biological deficiency and the clinical alterations (pulmonary, cutaneous and articular) could be assumed according to the biological and ultrastructural findings.

Adult↗
PubMed2026

Modelling time-varying genetic effects on binary disease risk via functional Mendelian randomization.

MOTIVATION: Genome-wide association studies have identified thousands of genetic variants associated with complex traits, establishing Mendelian randomization (MR) as a powerful framework for causal inference using variants as natural experiments. However, existing MR methods treat causal effects as static, relying on cross-sectional exposure measurements and ignoring how genetic predispositions to disease operate dynamically across the life course. Recovering age-specific causal effect functions from longitudinal data requires combining functional data representations of exposure trajectories with instrumental variable estimation strategies suitable for binary disease endpoints, a methodological gap that has remained unaddressed. RESULTS: We develop a functional MR framework for binary outcomes that integrates functional principal component analysis with two-stage residual inclusion (2SRI), ensuring consistent estimation under the nonlinear logistic link function that renders standard instrumental variable estimators inconsistent. Simulations across different causal effect trajectory shapes, varying measurement densities, and varying instrument strengths demonstrate accurate recovery of time-varying genetically predicted effects with minimal bias. Applied to UK Biobank data, the framework identifies an age-specific causal effect of genetically predicted body mass index on type 2 diabetes risk concentrated in early mid-adulthood and progressively attenuating thereafter. Concordance between the proposed 2SRI estimator applied to type 2 diabetes and the established continuous-outcome functional MR estimator applied to the paired glycated haemoglobin marker in the same cohort provides indirect empirical support for the validity of the proposed approach. AVAILABILITY AND IMPLEMENTATION: The method is implemented in the R package mvfmr, with a full tutorial vignette.

Mendelian Randomization Analysis↗
PubMed2025

Genetic predisposition and mediating pathways in ischemic stroke-induced cardiac arrhythmias: a genome-wide analysis.

INTRODUCTION: The clinical presentation of stroke-heart syndrome (SHS) underscores the interplay between the central nervous system and the cardiovascular system. While cardiac arrhythmia is the prevalent form of cardiac injury in SHS patients, the causal link between ischemic stroke and cardiac arrhythmia is still unclear. METHODS: Mendelian randomization analyses and genome-wide association studies data were used to investigate the causal role of ischemic stroke on cardiac complications. Mediation and colocalization analyses were used to identify potential pathways and shared genetic variants. Single nucleotide polymorphisms (SNPs) associated with arrhythmias and ischemic stroke were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Gene expression omnibus (GEO) database from atrial fibrillation patients were used for validation. RESULTS: Mendelian randomization analyses showed a strong correlation between arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, with ischemic stroke. Diabetic microvascular (nephropathy, retinopathy) and macrovascular (cardiomyopathy, peripheral arterial disease) complications significantly mediated the effect of ischemic stroke on cardiac arrhythmias and atrial fibrillation, explaining 28.69&#xa0;% and 20.48&#xa0;% of the indirect effect, respectively. Colocalization analyses identified a shared causal variant in the Phosphodiesterase 3A (PDE3A) gene (rs11045239), providing genetic evidence for a shared pathogenic pathway between ischemic stroke and cardiac arrhythmias. Moreover, KEGG pathway enrichment analyses identified a role of the cyclic adenosine monophosphate (cAMP) signaling pathway in both ischemic stroke and arrhythmias. Validation using the GEO database confirmed a significant upregulation of the PDE3A gene expression in atrial fibrillation patients. CONCLUSION: This study demonstrated a causal link between ischemic stroke and cardiac arrhythmias, with diabetic complications as one mediating factor. The identification of a shared causal variant in the PDE3A gene and the role of the cAMP signaling pathway have the potential to improve prediction and management of SHS patients.

Humans↗
PubMedDate not supplied

[Hyperthyroidism in early childhood and a very rare variant of glutaric aciduria: coincidence or causal relation?].

Hyperthyrosis is a rare disease in early childhood typically characterized by tachycardia, restlessness, elevated body temperature, failure to thrive, diarrhoea, goiter and a tendency to hyperglycaemia. A 3-year old boy presented with typical symptoms of thyrotoxicosis accompanied by ketotic hypoglycemia and excessively high glutaric acid excretion. To our knowledge this association has so far not been described. Specific defects responsible for glutaric aciduria types I & II were excluded. Our patient suffered from glutaric aciduria type III which was described once and is characterized by mild metabolic signs.

Age Factors↗
PubMed1996

The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder.

In the present study, we evaluated the possible contribution of genetic variation of the serotonin 5-HT7 receptor to the development of schizophrenia and bipolar affective disorder. Cloning and characterization of exon-flanking intronic sequences enabled us to investigate the whole coding region and the exon-intron boundaries of the human 5-HT7 receptor gene. Using single-strand conformational analysis, we screened for presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic and 46 bipolar affective patients, as well as 46 healthy controls. We detected two rare naturally occurring receptor variants (Pro-279-Leu, Thr-92-Lys) and a silent nucleotide substitution (A-->G) at position +1233. The occurrence of the Pro-279-Leu and Thr-92-Lys substitutions was studied in an extended sample of patients (n = 462) and controls (n = 335). The Leu-279 variant was found in similar frequency in all groups, indicating that presence of this variant is not causally related to the development of schizophrenia or bipolar affective disorder. The Lys-92 variant was found in a single individual who suffered from bipolar affective disorder. Investigation of the patient's family revealed independent segregation between the Lys-92 variant and psychiatric illness. Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia.

Bipolar Disorder↗
PubMed1996

[Prion diseases and a new variant of Creutzfeldt-Jakob disease].

The causal link of a new variant of CJD (v-CJD) with bovine spongiform encephalopathy (BSE) has led to world-wide panic. BSE emerged in 1986 through dietary products contaminated with scrapie pathogen, BSE case reports increased in number up to 37,000/year in 1993, then declined in 1994 when the first case of v-CJD emerged. There is a 3-year gap between the emergence of BSE and the introduction of a ban on the use of specified bovine offal in human food. People might have consumed dietary products contaminated with BSE pathogen for the period. Species barrier which has protected human from being transmitted with sheep scrapie pathogen might not work so well in cow-to-human transmission as in sheep-to-human. There are familial forms and sporadic forms of human prion diseases. The familial prion diseases are always related to prion protein (PrP) gene mutations. Sporadic forms of prion diseases are composed of sporadic CJD, iatrogenic CJD and kuru. Sporadic CJD occurs in elder people and shows cortical signs and periodic synchronous discharges (PSD) in short clinical course and pathologically spongiform degeneration and abnormal PrP deposition in synapse structures, but no amyloid plaque deposition in the brain is observed. Since the v-CJD patients had no mutations in PrP gene, v-CJD belongs to sporadic forms of prion diseases. v-CJD shows quite different clinicopathological features from those of sporadic CJD, rather shows similar features to iatrogenic CJD of pituitary hormone and kuru. These three diseases share several features, which are younger patient age, main clinical manifestation of cerebellar signs, negative or rare record of PSD, and PrP amyloid plaque deposition in the brain. The patients of v-CJD, however, had no history of exposure to iatrogenic factors and of cannibalism. Also they did not have a valine polymorphism at PrP codon 129 which is frequently observed in the patients with iatrogenic CJD and kuru. Thus, v-CJD is a quite novel entity in human prion diseases.

Animals↗
PubMed2003

[Disease-causing mutations versus neutral polymorphism: use of bioinformatics and DNA diagnosis].

Molecular genetic diagnostics is available for increasing number of genetically determined diseases. A wide spectrum of mutations can be detected by laboratory methods. A mutation can be defined as a change in a specific DNA sequence when compared with the reference sequence published in the gene database. However, in some cases it is difficult to distinguish if the detected sequence variant is a causal mutation or a neutral (polymorphic) variation without any effect on phenotype. The interpretation of rare sequence variants of unknown significance detected in disease-causing genes becomes an increasingly important problem. Further analysis on DNA and on protein levels with the use of bioinformatics are needed to reveal the effect of rare sequence variants. Inherited complex disorders, for example rare hereditary forms of cancer diseases, represent a challenge to molecular geneticists. The identification of exact causal mutation directly responsible for the development of the disease and for the assessment of disease risk resulting from this genetic variation has further implications. Predictive genetic diagnostics allows identify relatives at high risk of genetically determined disease and use of targeted preventive and therapeutic approaches. In severe cases it allows also prenatal or pre-implantation diagnostics.

DNA Mutational Analysis↗