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At least 19 recordsLinked to original sources
PubMed1992

Studies on apolipoprotein(a) phenotypes. Part 2. Phenotype frequencies and Lp(a) concentrations in different phenotypes in patients with angiographically defined coronary artery diseases.

In the present paper, we have evaluated serum Lp(a) concentrations, the frequencies of Lp(a) phenotypes and alleles and the association between the Lp(a) phenotypes and serum Lp(a) levels in 470 patients with angiographically defined coronary artery disease (CAD). Serum Lp(a) concentrations were significantly increased in proportion to the number of diseased vessels in the CAD patients. The frequencies of Lp(a) phenotypes in the CAD patients were significantly different from those in healthy subjects. In particular, the frequency of double-band phenotypes was higher in the CAD group. The frequencies of Lp(a) alleles in the CAD patients, however, were not significantly different from those in the healthy subjects. There was a strong inverse relationship between the apparent molecular weights of apo(a) isoforms and serum Lp(a) concentrations. Lp(a) levels in the CAD patients were higher than those in the healthy subjects with the same phenotype. The present results suggest that it is important to consider some posttranslational or environmental modifications and other factors, in addition to the genetic factor, when assessing contributions to plasma Lp(a) levels.

Alleles↗
PubMed1992

Studies on apolipoprotein(a) phenotypes. Part 1. Phenotype frequencies in a healthy Japanese population.

The frequency distribution for serum lipoprotein(a) (Lp(a)) concentrations in healthy Japanese was highly skewed, with a mean +/- S.D. of 14.6 +/- 13.6 mg/dl and a median of 11.0 mg/dl. The present study provides the first evidence on the frequencies of Lp(a) phenotypes and alleles in healthy Japanese subjects. There was a strong inverse relationship between the apparent molecular weights of apo(a) isoforms and plasma Lp(a) concentrations, as reported previously. However, because of the considerable overlap between the Lp(a) concentrations of the different phenotypes, it was impossible to predict Lp(a) concentration from Lp(a) phenotypes, or vice versa. The present results suggest that the distribution of Lp(a) concentrations, mean and median values and Lp(a) phenotype and allele frequencies in healthy Japanese are not significantly different from the results for Europeans, whereas they are significantly different from other Asian populations, i.e. Chinese, Indians and Malaysians.

Adolescent↗
PubMed2025

Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer.

PURPOSE: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. METHODS: We collated clinical diagnostic testing data on germline FH variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of "very-rare" variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log2.08 likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework. RESULTS: For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 "hotspot" regions wherein the DS-VRMV-LR increased to 1226.9. CONCLUSION: These data provide quantitative measures for very rare missense and truncating variants in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification.

Humans↗
PubMed1992

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed1977

Classification of alpha1-antitrypsin (Pi) phenotypes by isoelectrofocusing. Distinction of six subtypes of the PiM phenotype.

Pi phenotypes have been determined by isoelectrofocusing in a sample of 538 healthy individuals from Southern Germany. Further subdivision of the common PiM phenotype is described. A procedure for the delineation of six common subtypes is presented. It is assumed that the six subtypes are determined by three alleles which are provisionally called PiMa, PiMb, and PiMc. Their frequencies in this sample were 0.75, 0.06, and 0.15, respectively.

Alleles↗
PubMed1975

Studies on an unstable phenotype induced by UV irradiation: the lysine excreting (lex(-)) phenotype of the yeast Saccharomycosis lipolytica.

Unstable clones excreting L-lysine into their growth medium are obtained at a very high frequency following UV irradiation in both haploid and diploid strains of Saccharomycopsis lipolytica, provided they carry a mutation affecting the first enzyme of the lysine pathway and confering resistance to end product inhibition. The phenotype can be stabilized in some sublines; it appears as dominant and coupled with a decrease in spore viability. Excretion in batch cultures is confined to the end of the exponential phase, and seems not to consist in a simple release of the lysine pool content.

Amino Acids↗
PubMed1992

Phenotypic and functional analysis of lymphocytes infiltrating paediatric tumours, with a characterization of the tumour phenotype.

Tumour-infiltrating lymphocytes (TIL) of paediatric tumours obtained from 37 lesions of different histotype (12 osteosarcomas, 5 Wilms' tumours, 7 soft-tissue sarcomas, 5 neuroblastomas and 8 miscellaneous) were studied to establish their potential for therapy. Fresh isolated TIL were cultured for the first 2 weeks with low doses of interleukin-2 (IL-2) (20 Cetus U/ml) to select for "tumour-specific" lymphocytes potentially present in the neoplastic lesion, followed by culture with high doses of IL-2 (1000 Cetus U/ml) to achieve TIL expansion. TIL were grown with more than 10-fold expansion in only 9 cases (mean expansion: 58-fold, range 13.5-346). In 17 cases no viable cells were obtained. After 30 days of culture with IL-2 the proliferative ability of TIL declined sharply in the majority of cases and TIL became refractory to any further stimulus, including addition of IL-4, tumour necrosis factor alpha (TNF alpha) or interferon gamma, and activation with OKT3 in solid phase. In 20 out of 37 cases TIL were available for phenotypic and functional analysis. TIL after long-term culture were predominantly CD3+ but 2 cases of osteosarcoma showed a predominance of CD3+TcR gamma/delta cells. The CD4/CD8 ratio was more than 1 in 10 cases, without correlation with tumour histology, site of lesion or TIL growth. The number of CD16+ and CD25+ lymphocytes decreased progressively during culture, the latter concomitantly with a reduction of TIL growth rate. The lytic pattern of TIL against allogenic and autologous tumour (Auto-Tu) cells was variable, but specific lysis of Auto-Tu was seen in only one case (Wilms' tumour) after culture with TNF alpha and irradiated Auto-Tu cells. The immunohistochemical analysis of tumour lesions revealed a limited lymphocyte infiltrate, a low expression of histocompatibility leukocyte antigens (HLA) class I and of the adhesion molecules ICAM1, LFA3, and a significant production of transforming growth factor beta (TGF beta). These data indicate that TIL obtained from paediatric patients are difficult to expand at levels required for immunotherapy and lack a significant number of tumour-specific T lymphocytes. A low expression of immunomodulatory molecules on tumour cells or the production of suppressive factors may prevent activation and expansion of TIL in paediatric tumours.

Antigens, CD↗
PubMed1992

Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus.

We describe an Ashkenazi Jewish family in which two adults, offspring of consanguineous parents, have persistent hypertyrosinaemia (770-1110 mumol/L; normal less than 110 mumol/L). The metabolic disorder in this family is apparently due to hepatic cytosolic tyrosine aminotransferase deficiency (hereditary tyrosinaemia, type II; McKusick, 276600), because it is associated with the oculocutaneous manifestations of Richner-Hanhart syndrome. The association of this syndrome with hereditary tyrosinaemia type II is presumed to be constant. It is not in this family. The affected female sib (age 41 years) has hypertyrosinaemia and oculocutaneous signs; the brother (age 39 years) has hypertyrosinemia but no oculocutaneous disease. Both sibs have two children; none has signs of a metabolic fetopathy. Maternal hypertyrosinaemia and maternal hyperphenylalaninaemia evidently constitute different risk factors for the fetus. Paternal hypertyrosinaemia is apparently not a risk to male infertility.

Adult↗
PubMedDate not supplied

Determination of phenotypes of esterases (Set) in fresh saliva and saliva stains by disc electrophoresis and the distribution of Set phenotypes in the Japanese population.

A rapid and simple disc electrophoretic technique for the determination of saliva esterase (Set) types is described. The frequency of Set types was F 16.4%, FS 49.8% and S 33.8%. The estimated gene frequency of Set-1F was 0.413 and of Set-1S was 0.587. An accurate determination of Set types was possible in 5--7 week-old saliva stains. This system may be useful in medicolegal applications.

Electrophoresis, Disc↗
PubMed2025

Optimized phenotyping of complex morphological traits: enhancing discovery of common and rare genetic variants.

Genotype-phenotype (G-P) analyses for complex morphological traits typically utilize simple, predetermined anatomical measures or features derived via unsupervised dimension reduction techniques (e.g. principal component analysis (PCA) or eigen-shapes). Despite the popularity of these approaches, they do not necessarily reveal axes of phenotypic variation that are genetically relevant. Therefore, we introduce a framework to optimize phenotyping for G-P analyses, such as genome-wide association studies (GWAS) of common variants or rare variant association studies (RVAS) of rare variants. Our strategy is two-fold: (i) we construct a multidimensional feature space spanning a wide range of phenotypic variation, and (ii) within this feature space, we use an optimization algorithm to search for directions or feature combinations that are genetically enriched. To test our approach, we examine human facial shape in the context of GWAS and RVAS. In GWAS, we optimize for phenotypes exhibiting high heritability, estimated from either family data or genomic relatedness measured in unrelated individuals. In RVAS, we optimize for the skewness of phenotype distributions, aiming to detect commingled distributions that suggest single or few genomic loci with major effects. We compare our approach with eigen-shapes as baseline in GWAS involving 8246 individuals of European ancestry and in gene-based tests of rare variants with a subset of 1906 individuals. After applying linkage disequilibrium score regression to our GWAS results, heritability-enriched phenotypes yielded the highest SNP heritability, followed by eigen-shapes, while commingling-based traits displayed the lowest SNP heritability. Heritability-enriched phenotypes also exhibited higher discovery rates, identifying the same number of independent genomic loci as eigen-shapes with a smaller effective number of traits. For RVAS, commingling-based traits resulted in more genes passing the exome-wide significance threshold than eigen-shapes, while heritability-enriched phenotypes lead to only a few associations. Overall, our results demonstrate that optimized phenotyping allows for the extraction of genetically relevant traits that can specifically enhance discovery efforts of common and rare variants, as evidenced by their increased power in facial GWAS and RVAS.

Humans↗
PubMed2026

Genetic Correlation Between Brain Imaging Phenotypes and Externalizing Behavior: A Large-Scale LDSC Analysis of UK Biobank IDPs.

Externalizing has been associated with differences in brain structure and function; however, it remains unclear whether these associations reflect shared common-variant genetic influences. Cross-trait linkage disequilibrium score regression was used to estimate genome-wide genetic correlations between externalizing genome-wide association study (GWAS) results and 3,935 brain imaging-derived phenotypes from the UK Biobank BIG40 resource. The imaging phenotypes covered structural magnetic resonance imaging (MRI), diffusion MRI, susceptibility-weighted imaging, resting-state functional MRI, and task-based functional MRI. Results were included in the primary analysis when the imaging phenotype had positive single-nucleotide polymorphism (SNP) heritability, a heritability Z statistic of at least 1.96, a mean GWAS chi-square statistic of at least 1.02, at least 200,000 regression SNPs, and a complete LDSC result without a fatal error. Technical imaging quality-control phenotypes were excluded from biological inference. Individual results were corrected using the Benjamini-Hochberg false discovery rate procedure. Aggregated Cauchy association tests (ACATs) were used to evaluate evidence across all imaging phenotypes and within predefined imaging categories. Statistical power, simultaneous confidence bounds, and alternative quality-control definitions were examined in sensitivity analyses. Of the 3,935 imaging phenotypes, 3,716 produced estimable genetic correlations, 2,980 met the primary LDSC quality-control criteria, and 2,967 were classified as biological imaging phenotypes. No individual phenotype survived false discovery rate correction. The smallest unadjusted P value was 0.0005, and the minimum adjusted q value was 0.486. The distribution of genetic correlations was centered near zero, with a median genetic correlation of 0.0014 and a median absolute genetic correlation of 0.0338. ACAT provided no evidence of an aggregate association across all biological imaging phenotypes (P = 0.302), and no predefined imaging category survived multiple-testing correction. The median minimum detectable genetic correlation at 80% power was 0.216. Bonferroni-adjusted simultaneous confidence intervals were fully contained within the interval [-0.30, 0.30] for 80.0% of phenotypes in the primary analysis and 88.0% under the stringent heritability quality-control definition. Broad and stringent sensitivity analyses produced the same overall conclusions. In this study, no statistically robust evidence of genome-wide genetic correlations between externalizing and individual UK Biobank brain imaging phenotypes was found. Nevertheless, small, localized, mixed-direction, or developmentally specific genetic effects remain possible.

Journal Article↗
PubMed2025

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically. METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes. RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without. CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Humans↗
PubMed1979

Response of variant hereditary angioedema phenotypes to danazol therapy. Genetic implications.

Hereditary angioedema (HAE), an auto-somal dominant disorder characterized by attacks of episodic edema is associated with decreased functional levels of the C1 esterase inhibitor. Approximately 85% of patients have lowered antigen levels of a normal inhibitor protein. 15% of patients have normal or elevated antigenic levels of functionless protein. We have examined the response to danazol therapy of patients with the variant HAE phenotypes possessing the abnormal protein in an effort to determine if these patients possess a normal structural C1 inhibitor allele. Four patients with a variant HAE phenotype were treated successfully with danazol. In two patients, distinguished by the presence of a functionless, albumin-bound, C1 inhibitor (phenotype 2), phenotypic analysis of the danazol response by bidirectional immunoelectrophoresis revealed the appearance of the normal C1 inhibitor gene product during danazol therapy. This relatively cathodal C1 inhibitor peak appears in conjunction with the development of nearly normal functional activity. All of the functional C1 inhibitory activity which appeared in the phenotype 2 treatment serum was associated with the electrophoretically normal inhibitor. This normal protein could be separated from the functionless inhibitor protein by immunoadsorption and molecular sieve chromatography. Danazol therapy of the two patients with an electrophoretically normal, functionless C1 inhibitor (phenotype 3) also resulted in a clinical remission associated with development of a significant increment in functional serum C1 inhibitory activity and C1 inhibitor protein. These findings demonstrate that these two HAE phenotypic variants are heterozygous for the normal serum C1 inhibitor, a finding which was not apparent before phenotypic analysis of this serum during danazol therapy. These data provide strong evidence for a basic similarity between the common form of HAE and its phenotypic variants. They also suggest that a structural gene lesion may result in the abnormalities of serum C1 inhibitor function and disease expression in all three of these HAE phenotypes.

Angioedema↗
PubMed2025

Divergent and stabilizing selection shape the phenotypic space of Arabidopsis thaliana.

Why do we observe some plant phenotypes but not others? The multivariate phenotypic space occupied by individuals or species often reveals both limits and phenotypes strikingly deviating from main syndromes. These observations are usually thought to indicate, respectively, inviable trait combinations and unique phenotypes adapted to specific environments. However, the evolutionary drivers underlying trait covariations often remain unclear. Here, we characterized the phenotypic space of Arabidopsis thaliana by comparing 713 wild accessions collected across the globe with 2,544 artificially-created recombinant individuals. This, combined with the detection of adaptive processes operating within species, allowed us to elucidate the roles of natural selection as a driver of phenotypic (co)variations within A. thaliana. We found that the phenotypic space of this species is constrained and driven by varying levels of divergent and stabilizing selection across different traits. Moreover, at the margins of the European geographic range, strong directional selection favored outlier phenotypes characterized by very late flowering and variation in a WRKY transcription factor gene. Genome analyses revealed that these extreme phenotypes may be explained by hybridization between ancestral and modern lineages of A. thaliana. Our findings demonstrate how interplays between population history and natural selection shape phenotypic diversity in a plant species.

Arabidopsis↗
PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗
PubMed1992

Lack of increase in heterozygous alpha 1-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma.

Homozygous alpha 1-antitrypsin deficiency (PiZZ phenotype) is known to be associated with increased risk of cirrhosis and primary liver cancer. Although a relationship between heterozygous alpha 1-antitrypsin deficiency and chronic liver disease was suggested recently, it is still a matter of controversy whether such patients are at increased risk of liver cancer. The goal of this study was to determine the prevalence of heterozygous alpha 1-antitrypsin deficiency of different phenotypes among patients with primary hepatobiliary cancers. We studied 82 patients with primary hepatobiliary cancer; 59 had hepatocellular carcinoma and 23 had bile duct carcinoma. alpha 1-Antitrypsin quantitation and phenotyping were performed in each patient using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds-ratio and chi 2 tests were used to measure the relative risk and the significance of association, respectively, between primary hepatobiliary cancers and heterozygous alpha 1-antitrypsin deficiency. Four patients in each of the cancer groups were heterozygous. Among the hepatocellular carcinoma patients, three had the PiMS phenotype and one had the PiMZ phenotype. Of these four heterozygous patients, only two had cirrhosis; one had cryptogenic cirrhosis and the other had hepatitis B virus-related cirrhosis. One noncirrhotic patient with a PiMZ phenotype had a fibrolamellar carcinoma. Of the four patients with bile duct carcinoma, three had the PiMS phenotype and one had the PiMZ phenotype. Of the four heterozygous patients, two had primary sclerosing cholangitis without associated inflammatory bowel disease and one patient had had previous biliary operations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗