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Christina G S Palmer

Publications and source records attributed to Christina G S Palmer.

15 recordsLinked to original sources
PubMed2024

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Humans↗
PubMed2006

Allowing for missing data at highly polymorphic genes when testing for maternal, offspring and maternal-fetal genotype incompatibility effects.

Genes can be associated with disease through an individual's inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene's functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring's genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test's performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.

Algorithms↗
PubMed2006

HLA-B maternal-fetal genotype matching increases risk of schizophrenia.

Schizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype-matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22-2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia.

Female↗
PubMed2006

The v-MFG test: investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability.

The MFG test is a family-based association test that detects genetic effects contributing to disease in offspring, including offspring allelic effects, maternal allelic effects and MFG incompatibility effects. Like many other family-based association tests, it assumes that the offspring survival and the offspring-parent genotypes are conditionally independent provided the offspring is affected. However, when the putative disease-increasing locus can affect another competing phenotype, for example, offspring viability, the conditional independence assumption fails and these tests could lead to incorrect conclusions regarding the role of the gene in disease. We propose the v-MFG test to adjust for the genetic effects on one phenotype, e.g., viability, when testing the effects of that locus on another phenotype, e.g., disease. Using genotype data from nuclear families containing parents and at least one affected offspring, the v-MFG test models the distribution of family genotypes conditional on offspring phenotypes. It simultaneously estimates genetic effects on two phenotypes, viability and disease. Simulations show that the v-MFG test produces accurate genetic effect estimates on disease as well as on viability under several different scenarios. It generates accurate type-I error rates and provides adequate power with moderate sample sizes to detect genetic effects on disease risk when viability is reduced. We demonstrate the v-MFG test with HLA-DRB1 data from study participants with rheumatoid arthritis (RA) and their parents, we show that the v-MFG test successfully detects an MFG incompatibility effect on RA while simultaneously adjusting for a possible viability loss.

Alleles↗
PubMed2005

An exact maternal-fetal genotype incompatibility (MFG) test.

The maternal-fetal genotype incompatibility (MFG) test can be used for a variety of genetic applications concerning disease risk in offspring including testing for the presence of alleles that act directly through offspring genotypes (child allelic effects), alleles that act through maternal genotypes (maternal allelic effects), or maternal-fetal genotype incompatibilities. The log-linear version of the MFG model divides the genotype data into many cells, where each cell represents one of the possible mother, father, and child genotype combinations. Currently, tests of hypotheses about different allelic effects are accomplished by an asymptotic MFG test, but it is unknown if this is appropriate under conditions that produce small cell counts. In this report, we develop an exact MFG test that is based on the permutation distribution of cell counts. We determine by simulation the type I error and power of both the exact MFG test and the asymptotic MFG test for four different biologically relevant scenarios: a test of child allelic effects in the presence of maternal allelic effects, a test of maternal allelic effects in the presence of child allelic effects, and tests of maternal-fetal genotype incompatibility with and without child allelic effects. These simulations show that, in general, the exact test is slightly conservative whereas the asymptotic test is slightly anti-conservative. However, the asymptotic MFG test produces significantly inflated type I error rates under conditions with extreme null allele frequencies and sample sizes of 75, 100, and 150. Under these conditions, the exact test is clearly preferred over the asymptotic test. Under all other conditions that we tested, the user can safely choose either the exact test or the asymptotic test.

Adult↗
PubMed2005

Evaluating the impact of genetic counseling and testing with signal detection methods.

One measure of the impact of genetic counseling and testing (GCT) is the extent to which it fosters behavioral change that is consistent with mutation status. We describe and illustrate how two different signal detection methods, receiver operating characteristic (ROC) analysis and recursive partitioning, can be used in this context to evaluate the impact of GCT. We analyzed real screening behavior data obtained in the 12 months following GCT for Hereditary Nonpolyposis Colon Cancer (HNPCC) using these two different signal detection approaches. Each approach demonstrated that GCT had an impact on behavioral outcomes, and was effective in fostering behavioral outcomes appropriate to mutation status. The ROC approach demonstrated that GCT was effective because mutation positive and mutation negative individuals could be distinguished on the basis of the number of recommended screening behaviors. The recursive partitioning approach demonstrated that GCT was effective because there were generally high rates of adherence to screening guidelines among subjects. The recursive partitioning technique also identified four subgroups of subjects, each with distinct characteristics, for which tailored interventions could be developed to increase rates of adherence to screening guidelines. Signal detection methods are easily implemented and are useful techniques for evaluating the impact of GCT.

Adult↗
PubMed2004

Colon cancer screening practices after genetic counseling and testing for hereditary nonpolyposis colorectal cancer.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colon cancer. Cancer screening recommendations differ between individuals identified to carry an HNPCC mutation and those who do not carry a known family mutation. We assessed the impact of genetic counseling and testing (GCT) on the use of endoscopic screening procedures and adherence to recommended endoscopic screening guidelines in 56 asymptomatic at-risk individuals from families known to carry an HNPCC mutation. PATIENTS AND METHODS: We analyzed data on colonoscopy and flexible sigmoidoscopy screenings collected before GCT and 6 months and 12 months post-GCT on 17 mutation-positive and 39 true mutation-negative individuals. Main outcome measures were use of endoscopic screening and adherence to recommended guidelines for the relevant mutation status. Mutation status, age, sex, employment, and income were analyzed as predictor variables. RESULTS: Among mutation-negative individuals, use of colonoscopy and flexible sigmoidoscopy decreased significantly between pre- and post-GCT (P <.00001 and P <.0003, respectively). Among mutation-positive individuals, a nonsignificant increase (P =.24) in use was noted. Age was also associated with use of endoscopic screening after GCT (P =.03). Mutation status (odds ratio [OR], 7.5; P =.02) and employment (OR, 8.6; P =.025) were associated with nonadherence to endoscopic screening guidelines. More mutation-negative individuals strictly adhered to guidelines than did mutation-positive individuals (87% v 65%). CONCLUSION: Genetic counseling and testing for HNPCC significantly influences the use of colonic endoscopy and adherence to recommendations for colon cancer screening.

Adult↗
PubMed2004

RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order.

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal-fetal genotype incompatibility (MFG) test used in an earlier case-parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.

Birth Order↗
PubMed2003

Genetic linkage and association between chromosome 1q and working memory function in schizophrenia.

Schizophrenia is substantially heritable, but specific susceptibility genes remain to be identified. Progress in this endeavor has been hindered by non-Mendelian transmission patterns, probable genetic heterogeneity, and an inability to detect premorbid and nonpenetrant carriers of predisposing genes. To circumvent these complexities, this study employed quantitative measures of liability, or "endophenotypes," within a sample of twins discordant for schizophrenia, drawn from the relatively genetically isolated population of Finland. A region on the distal portion of chromosome 1 has shown evidence for linkage to schizophrenia in two prior studies using Finnish patient samples. To elucidate further the nature and location of this potential susceptibility gene, linkage and association analyses were carried out across the chromosome 1 region of interest using quantitative neuropsychological measures of liability. Analyses with a composite measure of liability yielded suggestive evidence for linkage at marker D1S2833 (P = 0.04). Follow-up analyses of the individual trait measures showed that the Visual Span subtest of the Wechsler Memory Scale (WMS), an indicator of spatial working memory function, was uniquely sensitive to marker D1S2833 (P = 0.007). Association analysis confirmed that allelic variation in D1S2833 is associated with variation in spatial working memory performance as measured by the Visual Span subtest (P = 0.003), the significance of which was confirmed in an analysis of 10,000 Monte Carlo permutations. These data support the utility of this approach and provide evidence for a gene affecting spatial working memory function in schizophrenia patients and their unaffected co-twins.

Chromosomes, Human, Pair 1↗
PubMed2003

Detecting genotype combinations that increase risk for disease: maternal-fetal genotype incompatibility test.

Biological mechanisms that involve gene-by-environment interactions have been hypothesized to explain susceptibility to complex familial disorders. Current research provides compelling evidence that one environmental factor, which acts prenatally to increase susceptibility, arises from a maternal-fetal genotype incompatibility. Because it is genetic in origin, a maternal-fetal incompatibility is one possible source of an adverse environment that can be detected in genetic analyses and precisely studied, even years after the adverse environment was present. Existing statistical models and tests for gene detection are not optimal or even appropriate for identifying maternal-fetal genotype incompatibility loci that may increase the risk for complex disorders. We describe a new test, the maternal-fetal genotype incompatibility (MFG) test, that can be used with case-parent triad data (affected individuals and their parents) to identify loci for which a maternal-fetal genotype incompatibility increases the risk for disease. The MFG test adapts a log-linear approach for case-parent triads in order to detect maternal-fetal genotype incompatibility at a candidate locus, and allows the incompatibility effects to be estimated separately from direct effects of either the maternal or the child's genotype. Through simulations of two biologically plausible maternal-fetal genotype incompatibility scenarios, we show that the type-I error rate of the MFG test is appropriate, that the estimated parameters are accurate, and that the test is powerful enough to detect a maternal-fetal genotype incompatibility of moderate effect size.

Bias↗
PubMed2002

RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility.

Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.

Adult↗
PubMed2002

A genomewide scan for loci involved in attention-deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.

Alleles↗
PubMedDate not supplied

Attitudes of the broader hearing, deaf, and hard-of-hearing community toward genetic testing for deafness.

PURPOSE: To assess attitudes in a nonmedically and nonculturally influenced setting of reproductive-age adults toward genetic testing for deafness in newborns. METHODS: Hearing, deaf, and hard-of-hearing individuals at a university completed questionnaires assessing attitudes toward genetic testing. RESULTS: Eighty-five percent of hearing (n = 133) and 62% of deaf/hard-of-hearing (n = 89) individuals would allow genetic testing for deafness in their own newborn. CONCLUSIONS: These results indicate an acceptance of newborn genetic testing for deafness by individuals in the broader community, regardless of hearing status.

Adult↗