Analysis of a Scottish founder effect narrows the TAPVR-1 gene interval to chromosome 4q12.
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Alleles↗
Biomedical subjects
Kenneth Ward
Publications and source records attributed to Kenneth Ward.
Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension.
BACKGROUND: Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-beta type II receptor gene, BMPR2, predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. METHODS AND RESULTS: We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations (P=0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. CONCLUSIONS: Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.
Adolescent↗
Microarray technology in obstetrics and gynecology: a guide for clinicians.
Microarrays can be constructed with dozens to millions of probes on their surface to allow high-throughput analyses of many biologic processes to be performed simultaneously on the same sample. Microarrays are now widely used for gene expression analysis, deoxyribonucleic acid resequencing, single-nucleotide polymorphism genotyping, and comparative genomic hybridization. Microarray technology is accelerating research in many fields and now microarrays are moving into clinical application. This review discusses the emerging role of microarrays in molecular diagnostics, pathogen detection, oncology, and pharmacogenomics.
Chromosome Mapping↗
The search for idiopathic scoliosis genes.
STUDY DESIGN: A cohort of 145 patients with adolescent idiopathic scoliosis (AIS) were identified and contacted to determine whether they had a family history of scoliosis. These results were submitted to an internal genealogical database to screen for potential connections to other AIS families. The severity and incidence of AIS in extended family groups were also analyzed. OBJECTIVES: Our objectives were to quantify the genetic effect in AIS, determine the expressivity and penetrance of AIS in large family groupings, and examine larger scoliosis pedigrees for evidence of multiple genes. SUMMARY OF BACKGROUND DATA: Previous reports have suggested an 80% connectedness among scoliosis families, but no clear evidence of multiple genes. It is not known if there are major gene(s). METHODS: A cohort of 145 AIS probands were identified and contacted to ascertain whether they had a family history of AIS. Their medical records and spine radiographs were reviewed to confirm the diagnosis and determine the disease severity. Using an internal genealogical database, the cases were screened for potential connections that would produce larger extended pedigrees. RESULTS: Overall, 131 of the probands were in the database and 127 showed connections to other scoliosis families, a 97% connectedness. These results suggest a major scoliosis gene, as more than 50% of the probands were connected by founders that all resided in England in the mid 1500s. The differences in penetrance (41% vs. 34%) and expressivity (38% vs. 61%) between seemingly unrelated large family groupings might suggest that two different genes are a major influence for AIS in these families. CONCLUSIONS: Nearly all (97%) AIS patients have familial origins. There appears to be at least one major gene, and the differences in penetrance and expressivity in two large unconnected pedigrees might suggest the presence of more than one gene.
Cohort Studies↗
Microarray technology in biomedical research.
Microarrays have dozens to millions of probes attached to an inert surface allowing high-throughput analyses of many biologic processes to be performed simultaneously on the same sample. Microarrays with nucleic acid probes are now widely used for gene expression analysis, DNA re-sequencing, single nucleotide polymorphism genotyping, and comparative genomic hybridization. This technology is accelerating research in many fields and now microarrays are moving into clinical application. This review discusses how the microarray facility at the new Kaka'ako campus of the John A. Burns School of Medicine will impact molecular diagnostics, pathogen detection, oncology, and pharmacogenomics.
Biomedical Research↗
Differences in inflammatory cytokine and Toll-like receptor genes and bacterial vaginosis in pregnancy.
OBJECTIVE: This study was undertaken to estimate the frequency of inflammatory cytokine and Toll-like receptor gene polymorphisms in women with and without bacterial vaginosis (BV) in pregnancy. STUDY DESIGN: A secondary analysis was performed of pregnant women at less than 30 weeks' gestation enrolled as part of 2 multicenter studies. Eight hundred eighty-five women were assessed for BV (defined as Nugent's vaginal Gram stain score 7-10 and a pH > 4.5). Comparisons were made between women with or without BV. Extracted maternal DNA was analyzed for 7 cytokine (interleukin [IL] 1beta-511, IL1beta Exon 5 +3954, IL6-174, IL8-845, IL10-1082, tumor necrosis factor alpha-238 [TNFalpha-238], TNFalpha-308) and 2 Toll-like receptor (TLR-4 299, TLR-4 399) gene polymorphisms. RESULTS: BV was diagnosed in 497 women and 388 did not have BV. Genotype and allele frequency analyses revealed associations with BV and polymorphisms at the IL1beta Exon 5 +3954, IL6-174, IL10-1082, and TLR-4 399 loci. Women with BV were less likely to be homozygous (C/C) for IL1beta Exon 5 +3954 (P = .04). Women with BV were also less likely to have polymorphisms at the IL10-1082 (P = .03) and TLR-4 399 (P = .04) loci in the univariate analysis. Women with BV were more likely to be heterozygous (G/C) for the IL6-174 genotype (P < .0001). Multivariate analysis, controlling for maternal race, confirmed the following associations with BV: IL1beta Exon 5 +3954 (odds Ratio [OR] 0.5, 95% CI 0.3-0.9) and IL6-174 (OR 2.2, 95% CI 1.6-3.1). In addition, polymorphism at the IL8-845 locus was associated with a decreased risk for BV (OR 0.6, 95% CI 0.4-1.0). CONCLUSION: After controlling for race, polymorphisms at the IL1beta Exon 5 +3954, IL6-174, and IL8-845 loci were associated with an altered rate of BV in pregnancy.
Adult↗
The implication of de novo 21-hydroxylase mutation in clinical and prenatal molecular diagnoses.
We studied 37 unrelated families with a history of 21-hydroxylase deficiency (CYP21D) for eight common mutations and gene deletions in the 21-hydroxylase (CYP21) gene. We found de novo mutations in the CYP21 gene in two CYP21D patients. Analysis for eight common mutations in the 21-hydroxylase gene as well as large gene deletions was accomplished using polymerase chain reaction (PCR) followed by amplified created restriction site (ACRS) or restriction fragment length polymorphism (RFLP) and Southern blot followed by hybridization to a CYP21-specific probe. Linkage analysis was performed using microsatellite markers flanking the CYP21 gene. Ten short tandem repeat (STR) markers were used to confirm parentage in the two de novo mutation cases. In two prenatal diagnosis cases, an intron 2-13A/C>G mutation was identified in the proband, but not in the fetus, although the proband and fetus had identical linkage markers. Subsequently, the mutation was confirmed to be absent in the parents' genome and misparentage was ruled out. Our findings are consistent with previous studies showing a de novo mutation frequency of approximately 1.0-1.5% in the CYP21 gene. This new mutation rate is high relative to the rate of approximately one in one million for other autosomal recessive disorders. Thus, the de novo mutation rate in the CYP21 gene is not negligible. It must be considered and discussed in prenatal diagnosis and genetic counseling for this relatively common inherited disorder.
Adrenal Hyperplasia, Congenital↗
The heritability of preterm delivery.
OBJECTIVE: To study the heritability of preterm delivery. METHODS: Women who delivered a singleton infant at less than 36 weeks of gestation were asked about their family history. Twenty-eight families were identified in which the proband had at least five first- or second-degree relatives with preterm delivery. An extensive genealogy database (GenDB) was constructed using more than 9,000 genealogy sources in the public domain (records before 1929). GenDB documents the relationships between more than 17.5 million ancestors and 3.5 million descendants of approximately 10,000 individuals who moved to Utah in the mid 1800s. This database was searched for the names, birth dates, and birthplaces of the four grandparents for each of the 28 probands. Pairwise coefficients of kinship were determined for the 93 preterm delivery grandparents identified, and for sets of 100 individuals born in the 1920s who were randomly selected from the population database. RESULTS: Probands had a mean of 3.3 grandparents included in this database. The average coefficient of kinship for controls was 1.5 x 10(6) (standard deviation = 0.6 x 10(6)). This measure agrees with previous calculations for the Utah population. The coefficient of kinship for familial preterm delivery grandparents was more than 50 standard deviations higher (3.4 x 10(5) [P < .001]). CONCLUSION: This study confirms the familial nature of preterm delivery. On average, gravidae randomly selected from our population are 23rd degree relatives, while these preterm delivery probands are eighth-degree relatives. A genome-wide scan using these affected families is underway.
Adolescent↗
Homocysteine levels in women with antiphospholipid syndrome and normal fertile controls.
OBJECTIVE: Recent studies have identified hyperhomocysteinemia as a risk factor for both recurrent pregnancy loss and thrombosis. Antiphospholipid syndrome, an autoimmune disorder, is also characterized by recurrent pregnancy loss and thrombosis. Thus, our purpose was to determine if hyperhomocysteinemia is more common in patients with APS than normal fertile controls. METHODS: Plasma, sera and whole blood were obtained from two groups of women: (1) 22 with well-characterized antiphospholipid syndrome; and (2) 41 healthy fertile controls. Levels of fasting homocysteine, vitamin B16, vitamin B12, folate and the incidence of the C677/T mutation of the methylene tetrahydrofolate reductase genotype (C677T/MTHFR) were determined. RESULTS: The proportion of individuals with hyperhomocysteinemia and fasting plasma homocysteine levels were similar in women with APS and controls. Levels of vitamin B6, vitamin B12, folate and the incidence of C677/MTHFR were also similar in the two groups. CONCLUSION: Hyperhomocyteinemia and the C677T/MTHFR mutation are not common in women with antiphospholipid syndrome. Abnormal homocysteine metabolism is unlikely to play a major role in the pathogenesis of antiphospholipid syndrome.
Adult↗
Posttraumatic pseudotumor cerebri in a 4-year-old female.
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Accidental Falls↗
Splenic artery embolization as emergency treatment of splenic rupture in a child with T-cell acute lymphocytic leukemia having t(8;14) translocation.
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Angiography↗
A molecular variant of angiotensinogen is associated with idiopathic intrauterine growth restriction.
OBJECTIVE: Intrauterine growth restriction has been associated with failed maternal physiologic changes such as abnormal spiral artery remodeling and reduced maternal blood volume. A polymorphism of angiotensinogen Thr235 has been considered a risk factor for preeclampsia. We genotyped maternal and fetal deoxyribonucleic acid (DNA) for angiotensinogen Thr235 to estimate whether the polymorphism is also a risk factor for intrauterine growth restriction. METHODS: We examined maternal blood DNA in 174 patients with intrauterine growth restriction and 60 patients with both preeclampsia and intrauterine growth restriction. The control group comprised 400 consecutive cases of women with term pregnancies and infants with birth weight between the fifth and 95th percentiles. We also examined 162 DNA samples from fetal blood with intrauterine growth restriction for the Thr235 polymorphism, and 240 normal fetuses were used as the control group. The angiotensinogen genotype was determined using mutagenically separated polymerase chain reaction. The products were size fractionated on an agarose gel. Angiotensinogen genotypes were divided into three groups: MM (homozygous for angiotensinogen Met235 allele), TT (homozygous for angiotensinogen Thr235 allele), and MT (heterozygous). RESULTS: Maternal genotyping revealed a significantly higher Thr235 allele frequency in intrauterine growth restriction (.60) and preeclampsia/intrauterine growth restriction (.63) than in the control group (.36) (P <.001). Fetal genotyping revealed a Thr235 allele frequency of.59 in intrauterine growth restriction fetuses, as compared with the control group (.38) (P <.001). CONCLUSION: Maternal and fetal angiotensinogen Thr235 genotypes are associated with an increased risk of intrauterine growth restriction in our study population. The angiotensinogen Thr235 allele may predispose women to deliver growth-restricted fetuses.
Adolescent↗
Anticardiolipin and anti-beta2-glycoprotein-I antibodies in preeclampsia.
OBJECTIVE: To estimate whether antiphospholipid antibodies, specifically anticardiolipin and anti-beta(2)-glycoprotein-I antibodies, are associated with preeclampsia. METHODS: Plasma was prospectively obtained from four groups of pregnant women: those with 1) mild preeclampsia (n = 109); 2) severe preeclampsia (n = 134); 3) hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 57); and 4) normotensive controls (n = 100). Anticardiolipin and anti-beta(2)-glycoprotein-I levels were determined by enzyme-linked immunoassay. RESULTS: Subjects with mild preeclampsia, severe preeclampsia, and HELLP syndrome did not have significantly elevated levels of immunoglobulin G (IgG) and IgM anticardiolipin and anti-beta(2)-glycoprotein-I antibodies compared with normotensive controls (P >.05, Kruskal-Wallis). Similarly, subjects with mild preeclampsia, severe preeclampsia, and HELLP syndrome did not have a significantly higher proportion of women testing positive for each autoantibody compared with normotensive controls (chi(2)). The proportion of patients testing positive for anticardiolipin and anti-beta(2)-glycoprotein-I antibodies were similar in patients with preeclampsia developing before and after 34 weeks' gestation (chi(2)). CONCLUSION: Circulating levels of both anticardiolipin and anti-beta(2)-glycoprotein-I antibodies were not increased in patients with mild preeclampsia, severe preeclampsia, or HELLP syndrome compared with normotensive controls. Our data do not support routine testing for anticardiolipin and anti-beta(2)-glycoprotein-I antibodies in women with preeclampsia.
Adult↗
Genetic factors in preterm birth.
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Female↗
Renin and kallikrein in connecting tubule of mouse.
BACKGROUND: The observation of renin expression in connecting tubule, a segment that also expresses tissue kallikrein (KLK-1), raises two questions. Are the genes expressed in the same or in different cells of connecting tubule? Does this topography support the hypothesis that KLK-1 activates prorenin or is it more likely that it affords coordinated gene regulation? METHODS: Renin and KLK-1 were examined by immunostaining and in situ hybridization. Renin activation by KLK-1 was investigated in vitro. In vivo, excretion of prorenin and active renin was compared in mice homozygous for targeted inactivation of KLK-1 (TK(-/-)) and normal littermates (TK(+/+)). RESULTS: Using in situ immunostaining for renin and in situ hybridization for KLK-1 mRNA, we found that connecting tubule cells expressing renin also expressed KLK-1. We confirmed in vitro activation of prorenin by KLK-1, but found no difference in the ratio of active renin to prorenin in urine of TK(-/-) and TK(+/+) animals. Compared to TK(+/+) controls, TK(-/-) mice exhibited significantly lower 24-hour excretion of prorenin (5.05 +/- 1.16 mg Ang I/hour vs. 9.39 +/- 1.96 mg Ang I/hour, P < 0.05) and active renin (1.98 +/- 0.25 mg Ang I/hour vs. 3.58 +/- 0.39 mg Ang I/hour, P < 0.05), with no difference in either urine volumes or plasma renin concentrations. CONCLUSION: Direct interaction between renin and KLK-1, not ruled out in vitro, is not supported in vivo. By contrast, lower excretion of active renin and prorenin in TK(-/-) compared to TK(+/+) suggest coordinated regulation of the two proteins in their participation to collecting duct function.
Animals↗
Spinocerebellar ataxia in monozygotic twins.
CONTEXT: Although phenotypic heterogeneity in autosomal dominant spinocerebellar ataxia (SCA) has been explained in part by genotypic heterogeneity, clinical observations suggest the influence of additional factors. OBJECTIVES: To demonstrate, quantitate, and localize physiologic abnormalities attributable to nongenetic factors in the development of hereditary SCA. DESIGN: Quantitative assessments of ocular motor function and postural control in 2 sets of identical twins, one with SCA type 2 and the other with episodic ataxia type 2. SETTING: University laboratory. MAIN OUTCOME MEASURES: Saccadic velocity and amplitude, pursuit gain, and dynamic posturography. RESULTS: We found significant differences in saccade velocity, saccade metrics, and postural stability between each monozygotic twin. The differences point to differential involvement between twins of discrete regions in the cerebellum and brainstem. CONCLUSIONS: These results demonstrate the presence of quantitative differences in the severity, rate of progression, and regional central nervous system involvement in monozygotic twins with SCA that must be owing to the existence of nongermline or external factors.
Adult↗
Prenatal diagnosis of 21-hydroxylase deficiency caused by gene conversion and rearrangements: pitfalls and molecular diagnostic solutions.
OBJECTIVES: The present paper reports the prenatal diagnosis of congenital adrenal hyperplasia (CAH) in two cases of 21-hydroxylase deficiency. DNA diagnostic errors can be caused by the presence of the highly homologous 21-hydroxylase pseudogene, CYP21P, adjacent to the functional gene, CYP21. The present paper details how complex gene conversions and rearrangements between the CYP21 and CYP21P pose unique complications for prenatal diagnosis. METHODS: Analysis of eight common mutations in the 21-hydroxylase gene as well as deletion of the entire gene is accomplished using polymerase chin reaction (PCR) followed by amplified created restriction site (ACRS) or allele-specific oligohybridization (ASO) and Southern blot followed by hybridization to a CYP21-specific probe. Linkage analysis was performed using microsatellite markers flanking the CYP21 gene. RESULTS: The direct mutation detection assay indicated a complicated gene conversion and rearrangement in the probands of both families. Interpretation of these rearrangements made it difficult to determine whether or not the fetuses would be affected with CAH. Linkage studies revealed that each fetus had inherited both parental disease chromosomes and was therefore predicted to be affected with CAH. CONCLUSION: As observed in the two reported cases, direct DNA analysis may provide limited information due to gene conversion or rearrangement between the CYP21 and CYP21P genes. These cases suggest that direct mutation detection should be supported by linkage analysis, whenever possible, to provide more comprehensive information for the family.
Adrenal Hyperplasia, Congenital↗
Stillbirth: tissue findings with environmental and genetic links.
This article discusses stillbirth from a pathologist's perspective. Stillbirth may be caused by many different mechanisms. There are specific maternal and fetal disorders leading to stillbirth, and some of these have genetic and environmental associations. Frequently, an autopsy examination may determine the specific cause of the fetal death. We illustrate tissue findings in stillbirth to put individual faces on this condition.
Chromosome Aberrations↗