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PubMed2004

Population genetic variation in gene expression is associated with phenotypic variation in Saccharomyces cerevisiae.

BACKGROUND: The relationship between genetic variation in gene expression and phenotypic variation observable in nature is not well understood. Identifying how many phenotypes are associated with differences in gene expression and how many gene-expression differences are associated with a phenotype is important to understanding the molecular basis and evolution of complex traits. RESULTS: We compared levels of gene expression among nine natural isolates of Saccharomyces cerevisiae grown either in the presence or absence of copper sulfate. Of the nine strains, two show a reduced growth rate and two others are rust colored in the presence of copper sulfate. We identified 633 genes that show significant differences in expression among strains. Of these genes, 20 were correlated with resistance to copper sulfate and 24 were correlated with rust coloration. The function of these genes in combination with their expression pattern suggests the presence of both correlative and causative expression differences. But the majority of differentially expressed genes were not correlated with either phenotype and showed the same expression pattern both in the presence and absence of copper sulfate. To determine whether these expression differences may contribute to phenotypic variation under other environmental conditions, we examined one phenotype, freeze tolerance, predicted by the differential expression of the aquaporin gene AQY2. We found freeze tolerance is associated with the expression of AQY2. CONCLUSIONS: Gene expression differences provide substantial insight into the molecular basis of naturally occurring traits and can be used to predict environment dependent phenotypic variation.

Color↗
PubMed1998

Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine linked to the human leukocyte antigen phenotype of patients?

PURPOSE: An allogeneic polyvalent melanoma cell vaccine (PMCV) has been shown to be efficacious in improving overall survival of patients with malignant melanoma in a phase II clinical setting. The PMCV consists of three allogeneic melanoma cell lines. The objectives of the study were to determine (1) whether the survival of melanoma patients who received PMCV was related to the patient's human leukocyte antigen (HLA) class I phenotype matching the HLA class I phenotype of the PMCV, and (2) whether PMCV clinical efficacy was correlated to melanoma patients with a particular HLA phenotype(s). MATERIALS AND METHODS: PMCV was given to 69 melanoma patients with American Joint Committee on Cancer (AJCC) stage I to IV disease status. The PMCV and patients lymphocytes were typed for HLA-A and -B. A correlation was made between the HLA expression of PMCV lines and the HLA of patients to their survival status. A second correlation was made between the HLA of patients and survival independent of the PMCV HLA phenotype. RESULTS: Patients whose HLA phenotype (A3/11 and B7/44) matched the PMCV lines had a better overall survival (P < .029). Analysis of HLA expression of patients independent of PMCV HLA to survival showed that HLA-A25 phenotype patients had a significantly better overall survival (P = .006). HLA-B35 patients had a poorer survival outcome (P = .019). CONCLUSION: The studies indicate that overall survival following PMCV treatment in melanoma patients significantly correlates with their HLA phenotypes. These correlations may be related to the host immune response to the PMCV or due to differences in the clinical course of melanoma in patients with different HLA types.

Adult↗
PubMed1989

Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis--a complementation study involving cell lines from 19 patients.

Disorders of peroxisomal biogenesis include the Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum syndrome, and hyperpipecolic acidemia. These names were assigned before the recognition of the peroxisomal defect and the distinction between phenotypes is uncertain. Recent studies have identified at least four complementation groups, and indicate the presence of at least that number of distinct genotypes. The purpose of the present study was to examine the relationship between genotype and phenotype. We studied cultured skin fibroblasts from 19 patients in whom deficiency of peroxisomes had been established. Complementation analysis was performed with the criterion of complementation being the restoration of the capacity to synthesize plasmalogens when fibroblasts from two patients were fused. Six complementation groups were identified, and consisted of one 13 member group, one two member group, and four groups comprising single cases. The phenotype of each group was examined with respect to age of survival, clinical manifestations, and biochemical alterations. The 13 member group included patients with all of the four currently designated phenotypic entities, while the most common phenotype (Zellweger syndrome) was distributed among five of the six groups. We conclude that the currently used clinical categories do not represent distinct genotypes. Apparently different genes code for a similar phenotype and one defective gene may lead to variant phenotypes. Definitive classification and understanding of these disorders await definition of the specific biochemical defect in each of the genotypes.

Adrenoleukodystrophy↗
PubMed1991

Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice.

The functional immunological consequences of thymic regeneration after castration were studied in adult male C57Bl/6 mice. Phenotypic profiles of thymocytes present in the enlarged thymuses of castrate animals demonstrated a significant decrease in the proportion of thymocytes positive for the suppressor/cytotoxic phenotype (CD4-CD8+; P = 0.005). Thymic enlargement in castrate animals was accompanied by increased capacity of thymocytes to incorporate thymidine in response to Concanavalin A in vitro. Spleens from castrate mice also were enlarged, and in vitro generation of functional suppressor cells by splenocytes from castrate animals was decreased. Testosterone replacement resulted in thymic regression, with a shift toward expression of mature thymocyte phenotypes, a decrease in the double-positive phenotype (CD4+CD8+), and a relative predominance of the CD4-CD8+ suppressor/cytotoxic phenotype over the CD4+CD8- helper phenotype. Unstimulated thymidine incorporation by thymocytes from androgen-treated animals was decreased compared to controls (P = 0.050). Spleen size was not altered by androgen administration. These findings suggest that in the adult animal, changes in androgen status effect alterations in thymocyte phenotypic profiles and thymocyte function, with removal of androgens shifting the T cell balance toward the CD4 helper subset and administration of androgens changing the balance toward CD8 suppressor/cytotoxic T cell predominance.

Androgens↗
PubMed2005

Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J.

OBJECTIVE: To determine the phenotype variability associated with the specific C-terminal M-line titin mutation known to cause autosomal dominant distal myopathy, tibial muscular dystrophy (TMD; MIM 600334), and limb girdle muscular dystrophy 2J (LGMD2J). METHODS: Three hundred eighty-six individuals were genotyped for the Finnish founder mutation in titin (FINmaj) causing TMD/LGMD2J. RESULTS: Two hundred seven patients were heterozygous for the mutation. Among these patients, 189 (91%) had a more common phenotype compatible with the classic description of TMD. However, 18 (9%) had unusual phenotypes such as proximal leg or posterior lower leg muscle weakness and atrophy even at onset. Four patients were confirmed homozygotes representing the LGMD2J phenotype. These homozygotes were half of the eight LGMD patients previously described in the original large consanguineous kindred. CONCLUSIONS: Large variability of phenotypic expression caused by just one mutation, the Finnish FINmaj, suggests that no certain phenotype of myopathy/dystrophy can be excluded from being caused by mutated titin. Yet unknown homozygous or compound heterozygous titin mutations without phenotype in the heterozygote carriers may be responsible for undetermined recessive MD and LGMD.

Age of Onset↗
PubMed2004

Lack of association between oxidized LDL-cholesterol concentrations and haptoglobin phenotypes in healthy subjects.

BACKGROUND: The haptoglobin (Hp) 2-2 phenotype has been known to have less antioxidative activity than Hp 1-1 and Hp 2-1. However, few have reported the relationship between oxidative stress and Hp phenotypes by using oxidized LDL. The relationship between Hp phenotypes and oxidative stress was therefore investigated in healthy adults. METHODS: The serum Hp concentrations, albumin, uric acid, iron, L-ascorbic acid, total antioxidant status and oxidized LDL concentrations were measured and analysed in 200 healthy Korean men and women with Hp 2-1 and Hp 2-2 phenotypes. RESULTS: The serum concentrations of Hp were significantly higher in the Hp 2-1 compared with the Hp 2-2 phenotype. However, serum concentrations of total antioxidant status and oxidized LDL did not show any statistical differences in either sex. The L-ascorbic acid concentrations in serum showed lower values in the Hp 2-2 compared with the Hp 2-1 phenotype, for both sexes (P < 0.05). CONCLUSIONS: The concentration of L-ascorbic acid, the first line antioxidant, was lower in the Hp 2-2 than in the Hp 2-1 phenotype; this did not significantly affect the total antioxidant status, and there was no significant difference in oxidized LDL for either group in healthy adults.

Albumins↗
PubMed2003

Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype.

UNLABELLED: Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function. INTRODUCTION: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. MATERIALS AND METHODS: We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. RESULTS: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. CONCLUSION: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships.

Adolescent↗
PubMed2006

Understanding mammalian genetic systems: the challenge of phenotyping in the mouse.

Understanding mammalian genetic systems is predicated on the determination of the relationship between genetic variation and phenotype. Several international programmes are under way to deliver mutations in every gene in the mouse genome. The challenge for mouse geneticists is to develop approaches that will provide comprehensive phenotype datasets for these mouse mutant libraries. Several factors are critical to success in this endeavour. It will be important to catalogue assay and environment and where possible to adopt standardised procedures for phenotyping tests along with common environmental conditions to ensure comparable datasets of phenotypes. Moreover, the scale of the task underlines the need to invest in technological development improving both the speed and cost of phenotyping platforms. In addition, it will be necessary to develop new informatics standards that capture the phenotype assay as well as other factors, genetic and environmental, that impinge upon phenotype outcome.

Animals↗
PubMed2004

Selective phenotyping for increased efficiency in genetic mapping studies.

The power of a genetic mapping study depends on the heritability of the trait, the number of individuals included in the analysis, and the genetic dissimilarity among them. In experiments that involve microarrays or other complex physiological assays, phenotyping can be expensive and time-consuming and may impose limits on the sample size. A random selection of individuals may not provide sufficient power to detect linkage until a large sample size is reached. We present an algorithm for selecting a subset of individuals solely on the basis of genotype data that can achieve substantial improvements in sensitivity compared to a random sample of the same size. The selective phenotyping method involves preferentially selecting individuals to maximize their genotypic dissimilarity. Selective phenotyping is most effective when prior knowledge of genetic architecture allows us to focus on specific genetic regions. However, it can also provide modest improvements in efficiency when applied on a whole-genome basis. Importantly, selective phenotyping does not reduce the efficiency of mapping as compared to a random sample in regions that are not considered in the selection process. In contrast to selective genotyping, inferences based solely on a selectively phenotyped population of individuals are representative of the whole population. The substantial improvement introduced by selective phenotyping is particularly useful when phenotyping is difficult or costly and thus limits the sample size in a genetic mapping study.

Animals↗
PubMed2004

Simultaneous estimation of haplotype frequencies and quantitative trait parameters: applications to the test of association between phenotype and diplotype configuration.

The analysis of the haplotype-phenotype relationship has become more and more important. We have developed an algorithm, using individual genotypes at linked loci as well as their quantitative phenotypes, to estimate the parameters of the distribution of the phenotypes for subjects with and without a particular haplotype by an expectation-maximization (EM) algorithm. We assumed that the phenotype for a diplotype configuration follows a normal distribution. The algorithm simultaneously calculates the maximum likelihood (L0max) under the null hypothesis (i.e., nonassociation between the haplotype and phenotype), and the maximum likelihood (Lmax) under the alternative hypothesis (i.e., association between the haplotype and phenotype). Then we tested the association between the haplotype and the phenotype using a test statistic, -2 log(L0max/Lmax). The above algorithm along with some extensions for different modes of inheritance was implemented as a computer program, QTLHAPLO. Simulation studies using single-nucleotide polymorphism (SNP) genotypes have clarified that the estimation was very accurate when the linkage disequilibrium between linked loci was rather high. Empirical power using the simulated data was high enough. We applied QTLHAPLO for the analysis of the real data of the genotypes at the calpain 10 gene obtained from diabetic and control subjects in various laboratories.

Algorithms↗
PubMed2006

Evaluation of potential modifiers of the palatal phenotype in the 22q11.2 deletion syndrome.

OBJECTIVE: To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome. DESIGN: Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development. METHODS: The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants. RESULTS: The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase. CONCLUSIONS: Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2001

Impact of apolipoprotein(a) phenotypes on long-term renal transplant survival.

The long-term success of renal transplantation is limited because of chronic rejection (CR), which shows histologic parallels to atherosclerosis. Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis, but its role in CR has not been investigated. Plasma levels of Lp(a) are determined mainly by the inherited isoform (phenotype) of apolipoprotein(a) [apo(a)] and show an inverse correlation with the molecular weight of apo(a). Apo(a) isoforms were identified in frozen sera of 327 patients who received a renal transplant during 1982 to 1992. Long-term graft survival in recipients with high molecular weight (HMW) or low molecular weight (LMW) apo(a) phenotypes were compared retrospectively. Mean (95% confidence interval) transplant survival was 12.8 yr (range, 11.9 to 13.6 yr) in patients with HMW and 11.9 yr (range, 10.8 to 13.1 yr) in patients with LMW apo(a) phenotypes (P = 0.2065). In patients who were 35 yr or younger at the time of transplantation, mean transplant survival was more than 3 yr longer in recipients with HMW apo(a) phenotypes compared with those with LMW apo(a) phenotypes (13.2 yr [range, 12.1 to 14.4 yr] versus 9.9 yr (range, 8.5 to 11.5 yr); P = 0.0156). In a Cox's proportional hazards regression model, the presence of LMW phenotypes-but not gender, immunosuppression, or HLA mismatches-in young patients was associated with a statistically significant risk of CR (P = 0.0434). These retrospective data indicate that young renal transplant recipients with LMW apo(a) phenotypes have a significantly shorter long-term graft survival, regardless of the number of HLA mismatches, gender, or immunosuppressive treatment.

Adolescent↗
PubMed2000

Comparison of the phenotypes of Streptococcus zooepidemicus isolated from tonsils of healthy horses and specimens obtained from foals and donkeys with pneumonia.

OBJECTIVE: To determine whether streptococcal pneumonia is caused by strains of Streptococcus zooepidemicus similar to those obtained from the tonsils of healthy horses. SAMPLE POPULATION: 5 tonsils from healthy horses, 8 tracheal washes and 6 lung specimens from foals with pneumonia, and 5 nasopharyngeal swab specimens from donkeys with acute bronchopneumonia. PROCEDURE: Variable M-like protectively immunogenic SzP proteins of 5 isolates of S. zooepidemicus from each tonsil and clinical specimen were compared, using immunoblots. The SzP gene of 13 isolates representative of various SzP immunoblot phenotypes from 1 healthy horse and 9 horses and donkeys with pneumonia were sequenced and compared. Cell-associated hyaluronic acid concentration and resistance to phagocytosis of some isolates were measured. RESULTS: Tonsils of each healthy horse were colonized by several SzP phenotypes similar to those of foals or donkeys with pneumonia. In contrast, multiple isolates from animals with pneumonia had the same SzP phenotype, indicating infection by a single strain or clone. Analysis of the SzP sequence confirmed that differences in immunoblot phenotype were associated with sequence differences and that several SzP genotypes were in healthy horses and animals with pneumonia. Isolates with high concentrations of cell-associated hyaluronic acid were more resistant to phagocytosis. CONCLUSIONS AND CLINICAL RELEVANCE: An SzP-specific immunoblot is a useful, sensitive measure of diversity among strains of S. zooepidemicus. Single strains with SzP phenotypes similar to those found in tonsils of healthy horses cause pneumonia. Because of the diversity of SzP phenotype and genotype among isolates from animals with pneumonia, SzP phenotype is not an important determinant of invasiveness or epizootic capabilities.

Animals↗
PubMed1996

Effect of phenotypic expression of Brahman breeding on marbling and tenderness traits.

Steers with known proportions of Brahman and Hereford breeding (80 quarter-bloods, 25% Brahman x 75% Hereford and 79 half-bloods, 50% Brahman x 50% Hereford) were used to determine the effect of phenotype on marbling and beef tenderness characteristics. Three experienced evaluators independently classified each live steer according to estimated proportion of Brahman breeding based on phenotypic evidence of Brahman breed characteristics. The steers were slaughtered, their carcasses were graded, and a carcass. Samples of longissimus muscle were obtained for measurement of 24-h calpastatin activity, sensory panel evaluation, and Warner-Bratzler shear (WBS) force measurements. Paired steaks were aged (6 and 18 d postmortem) and palatability determinations were completed. Estimates of live animal phenotype ranged from 0/16 to 9/16 for quarter-blood Brahman steers and from 1/14 to 13/16 for half-blood Brahman steers. Neither live animal phenotype nor carcass hump height was correlated with marbling score. Live animal phenotype was correlated (P < .01) with taste panel tenderness ratings (rd6 = -.36; rd18 = .36) and shear force values (rd6 = .36; rd18 = .30). Moreover, carcass hump height exhibited low, negative correlations (P < .05) with panel tenderness scores (rd6 = -.16; rd18 = -.28) and low, positive correlations (P < .10) with shear force (rd6 = .13; rd18 = .16). Steaks from steers classified as more than 3/8 Brahman were tougher (P < .05) than steaks from steers classified as 3/8 or less Brahman. Steaks from carcasses with hump height measurements of 7.60 cm or greater had lower panel tenderness ratings and higher WBS values (P < .05) than steaks from carcasses with hump heights less than 6.35 cm. Quarter-blood and half-blood Brahman steers that were similar in phenotype produced steaks that were similar in tenderness. Results of this study suggest that as phenotypic evidence of Brahman breeding increases the tenderness of cooked steaks from Brahman crossbred steers decreases.

Animals↗
PubMed1989

Chronic antral gastritis, Lewis(a+) phenotype, and male sex as factors in predicting coexisting duodenal ulcer.

Chronic antral gastritis, Lewis(a+) phenotype (Le(a+)), and male sex are common in patients with peptic ulcer. To approximate the relative risks (RR) and possible interactions of these factors in predicting coexisting active duodenal (DU) or gastric ulcer (GU), a consecutive endoscopic series of 140 ulcer patients and 215 non-ulcer controls was examined. The Lea phenotype (Le(a+) versus Le(a-)) was determined immunohistochemically as binding of Le(a)+-specific monoclonal antibody to surface epithelial secretory mucosubstances in gastric biopsy specimens. The presence versus absence of the gastritis was determined histologically from antral specimens. The RRs of the factors in the prediction of ulcer were approximated as age-adjusted RRs when the risk of ulcer in the absence of the factors--that is, in the absence of gastritis, in female sex and in Le(a-) phenotype--was applied as a base line (RR = 1). A case-control design, logistic linear modelling, and the maximal likelihood method were used in estimation of the risks. The RR of coexisting distal ulcer (DU or pyloric or prepyloric GU) was increased in the presence of gastritis (RR = 10.2), in male sex (RR = 3.0), and in Le(a+) phenotype (RR = 1.8). The RR of proximal ulcer (angular or corpus GU) was increased in the presence of gastritis (RR = 35) but decreased in the presence of male sex (RR = 0.5) and Le(a+) phenotype (RR = 0.7). As predictors of both distal and proximal ulcer, gastritis, sex, and Le(a) phenotype were independent of each other; that is, their joint value in prediction of ulcer is a multiplicand of the marginal risks. Thus, a 50-fold difference in the joint RR could be approximated between the extreme risk groups for distal ulcer--that is, between Le(a+) males with gastritis and Le(-a) females with normal antrum. In a consecutive series of outpatient endoscopies, 45% of females and 8% of males could be categorized to these extreme 'low'- and 'high'-risk groups, respectively. We conclude that sex, Le(a) phenotype, and gastritis are factors that, at least in ordinary outpatient endoscopy material, divide subjects to subgroups with very different risks and probabilities for having coexisting peptic ulcer.

Adult↗
PubMed1992

Genetic epidemiology of low-density lipoprotein subclass phenotypes.

Heterogeneity in LDL particles can be described by two distinct phenotypes in individual subjects, denoted A and B, based on gradient gel electrophoresis. Phenotype A is characterized by a predominance of large, buoyant LDL particles, while phenotype B is characterized by a predominance of small, dense LDL particles. Several studies have demonstrated that LDL subclass phenotype B is associated with both increased risk of coronary heart disease and an atherogenic lipoprotein profile. Complex segregation analyses in families, heritability analyses in twins, and recent linkage analyses, uniformly support the presence of genetic influences on LDL subclass phenotypes. However, environmental and behavioural influences on LDL subclasses have also been documented. Understanding the mechanisms underlying LDL subclass phenotypes may lead to targeted intervention to reduce coronary heart disease (CHD) risk in genetically susceptible individuals. Thus, LDL subclass phenotypes represent a common, genetically-influenced risk factor for coronary heart disease.

Arteriosclerosis↗
PubMed2005

Phenotypic diversity in patients with craniosynostoses unrelated to Apert syndrome: the role of fibroblast growth factor receptor gene mutations.

OBJECT: The goal of this study was to elucidate the genotype-phenotype relationship in syndromic craniosynostoses by analyzing the mutations of the fibroblast growth factor receptor (FGFR) gene and its clinical manifestations in patients, particularly those in atypical cases. METHODS: Twenty patients with craniosynostoses unrelated to Apert syndrome were enrolled in this study. The phenotypes indicated the following syndromes: 12 patients with unrelated Crouzon syndrome, including nine sporadic and three familial cases; two with sporadic Pfeiffer syndrome; and one with Antley-Bixler syndrome. The Crouzon phenotype was subdivided into three clinical forms: regular, top, and bottom ones. Two patients who demonstrated craniofacial anomalies and bilateral elbow joint contractures were categorized as having an unspecified craniosynostosis. Three cases of unclassifiable cloverleaf skull malformation were also analyzed. Fourteen mutations of the FGFR2 gene were identified in these patients; seven of the 10 cysteine-related mutations were substitutions of codon 342 in the third immunoglobulin-like domain of this gene. The phenotypes of these seven cases were three of regular Crouzon, two of unspecified craniosynostosis, and one each of top Crouzon and unclassifiable cloverleaf skull malformation. In addition, four of the seven patients were found to have the same genotype (Cys342Arg). The phenotypes of these patients, however, were quite variable, ranging from regular Crouzon to unclassifiable cloverleaf skull malformation. CONCLUSIONS: The phenotypes of patients with craniosynostoses unrelated to Apert syndrome proved quite variable, even in cases in which patients demonstrated the same genotype. In view of the phenotypic diversity evident in cases in which the same mutation in the FGFR2 gene is present, it is possible that other disease-modifying genetic factors exist to control the abnormal gain-of-function that accompanies FGFR signaling.

Adolescent↗
PubMed2000

Policies and procedures related to weak D phenotype testing and Rh immune globulin administration. Results from supplementary questions to the Comprehensive Transfusion Medicine Survey of the College of American Pathologists.

OBJECTIVE: To determine and evaluate policies and procedures related to weak D phenotype testing and terminology and the administration of Rh immune globulin in selected clinical situations. Design, Setting, and Participants.-Institutions participating in the College of American Pathologists 1999 J-A Comprehensive Transfusion Medicine Survey program were asked to respond to a series of supplementary questions related to weak D phenotype testing and Rh immune globulin administration. More than 3500 institutions and transfusion services participated. RESULTS: Most supplementary questions elicited more than 3000 responses. Despite no clinical or regulatory mandate, 58. 2% of transfusion services routinely perform an antiglobulin test for the weak D phenotype in patients who test negative with anti-D reagents. Significant differences were found concerning the transfusion of blood components to patients with the weak D phenotype and the administration of Rh immune globulin to these individuals. At least one patient with the weak D phenotype with anti-D alloantibody formation was observed during a 12-month period by 31.8% of transfusion services. CONCLUSIONS: Significant variability concerning policies and procedures related to weak D typing and terminology was found in this survey. Transfusion of blood components to patients with the weak D phenotype and the administration of Rh immune globulin also demonstrated variations. Anti-D alloantibody formation by patients with the weak D phenotype may not be as rare as previously thought. Additional study related to the clinical significance of these results is warranted.

Blood Banks↗