Sudden infant death syndrome: Case-control frequency differences in paired like homeobox (PHOX) 2B gene.
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Alleles↗
Biomedical subjects
Margaret E Cooper
Publications and source records attributed to Margaret E Cooper.
Candidate genes for oral-facial clefts in Guatemalan families.
Nonsyndromic cleft lip +/- cleft palate (CL/P) is a complex trait of unknown etiology. Most genetic studies of CL/P define affection status in a way that ignores subtle subclinical manifestations, resulting in a potential loss of statistical power. This study investigated 10 candidate genes in 155 individuals from 25 Guatemalan CL/P families. High-resolution ultrasound images of the orbicularis oris (OO) muscle were obtained. CL/P was present in 28 family members; an additional 10 had subcutaneous OO muscle defects. Family-based association studies were performed for both narrow (CL/P only) and broad (CL/P plus OO muscle defects) definitions of affection status. PVRL1 was significantly associated under both definitions (P = 0.04, narrow; P = 0.02, broad). Association with JAG2 improved from P = 0.09 under the narrow definition to P = 0.04 under the broad definition. Broadening the oral-facial cleft phenotype to include subclinical variants may improve power in genetic studies.
Chromosome Aberrations↗
Asian oral-facial cleft birth prevalence.
OBJECTIVE: To determine the clefting birth prevalence among Asian populations, specifically Chinese and Japanese, using raw counts from nonoverlapping published studies of Asian populations, and to investigate whether Asian clefting rates have been interpreted accurately as being up to twice the Caucasian rate. DESIGN: A literature review of articles giving raw counts of clefting in Asian populations, primarily Japanese and Chinese. MAIN OUTCOME MEASURES: Where possible, clefts were identified by the patients' ethnicity, country of origin, cleft type, syndromic status, and birth status. RESULTS: Prevalence rates of cleft lip with or without cleft palate per 1000 live births are reported. Syndromic plus nonsyndromic cleft lip with or without cleft palate: Chinese, 1.30; Japanese, 1.34; Other Asian, 1.47; and total, 1.33. Nonsyndromic cleft lip with or without cleft palate: Chinese, 1.20; Japanese, 1.18; Other Asian, 1.22; and total, 1.19. CONCLUSIONS: Overall, Chinese and Japanese live birth prevalence rates for nonsyndromic cleft lip with or without cleft palate, based on the published reports of birth prevalence, are significantly lower than the oft-quoted rate of 2 per 1000 for Asians. The apparent reason for the discrepancy is that many published prevalence rates included all pregnancies (live births plus pregnancy losses) and do not distinguish between syndromic and nonsyndromic clefts or between cleft palate alone and cleft lip with or without cleft palate. These results demonstrate that it is extremely important for current population-based studies of clefts to include careful delineation of population groups, syndromes, cleft type, and birth status.
Asian People↗
Methods for detecting gene x gene interaction in multiplex extended pedigrees.
Complex diseases are multifactorial in nature and can involve multiple loci with gene x gene and gene x environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene x gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem.
Epistasis, Genetic↗
Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations.
In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6-7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160-167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287-294 cM, including D2), chromosome 5 (p-value < 0.001 for 0-7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7-14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage.
Chromosomes, Human↗
Protecting a veterinary grave in Kenya.
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Burial↗
Studies of reduced folate carrier 1 (RFC1) A80G and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with neural tube and orofacial cleft defects.
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Alleles↗
Bilateral asymmetry in Chinese families with cleft lip with or without cleft palate.
OBJECTIVE: To determine if Chinese individuals with nonsyndromic cleft lip with or without cleft palate (CL/P) display more bilateral asymmetry than do their unaffected relatives. DESIGN/SUBJECTS: A case-control study of 313 individuals with CL/P from Shanghai, China, with 201 unaffected relatives as controls. METHODS: Size-adjusted asymmetry scores were defined by data on middle-finger length, palm length, palpebral fissure width, and ear length. Case-control comparisons used a multivariate repeated measures analysis of variance, paired t tests, and the Wilcoxon signed rank test. RESULTS: The ear-length measure showed a significant increase in fluctuating asymmetry (FA) in individuals with CL/P compared with their unaffected relatives, which was most pronounced in the female cleft lip and palate subgroup (p = .04). No other measures showed any increase in FA. CONCLUSION: Evidence was found for increased FA, as measured by overall ear length, in Chinese individuals with nonsyndromic CL/P, compared with their unaffected family members. The use of bilateral measurements other than dermatoglyphics may prove to be a valuable means of assessing overall developmental stability in individuals with developmental malformations and in their families.
Analysis of Variance↗
Genome scan for loci involved in nonsyndromic cleft lip with or without cleft palate in families from West Bengal, India.
In order to identify genes or regions involved in nonsyndromic cleft lip with or without cleft palate (CL/P) in families from India, we analyzed 38 multiplex families (DNA from 272 individuals, 82 affected with CL/P, 190 unaffected) for 285 genome-wide markers (average spacing 12.6 cM), including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 that have been implicated in other studies of CL/P. LOD scores (two-point and multipoint), and model-free association (TDT) and linkage (NPL) statistics, were calculated between each of the markers and a hypothetical CL/P susceptibility locus. The most statistically significant two-point linkage results were with markers on chromosome 7 (LOD = 1.89 with D7S435, 7p15, 47 cM), chromosome 5 (LOD = 1.76 with D5S407, 5q11, 65 cM), chromosome 15 (LOD = 1.55 with D15S652, 15q26, 90 cM), and chromosome 20 (LOD = 1.46 with STS155130, 20q13, 54 cM). The most significant multipoint linkage result was on chromosome 5q, again near D5S407 (HLOD = 1.40). Regions on chromosomes 1p, 1q, 7q, 12q, 16q, 18q, and Xp also had a LOD or HLOD > or = 1.0. Of seven candidate markers and regions with previous positive reports in the literature (TGFA, MSX1, D4S175, F13A1, TGFB3, D17S250, and APOC2), none had a significant linkage result, but one (the APOC2 region) had a significant association result and three others (TGFA, MSX1, F13A1) had suggestive results. The results are consistent with the involvement of multiple loci in CL/P expression in this West Bengal population, which concurs with results found in other CL/P study populations.
Alleles↗
Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.
BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.
Cleft Lip↗
Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35.
Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.
Chromosomes, Human, Pair 2↗
Genome-scan for loci involved in cleft lip with or without cleft palate in consanguineous families from Turkey.
Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, with birth prevalence ranging from 1/500 to 1/1,000. A number of genetic loci have shown positive linkage or association results in European Caucasian populations. The purpose of the current study was to assess whether any of those loci have positive results in Turkish Caucasian CL/P families, and to perform a 10 cM genome scan to identify other regions potentially containing cleft susceptibility loci. Eighteen affected individuals with consanguineous parents were identified as part of our on-going studies of orofacial clefts in Ankara, Turkey. Genotyped were 383 genome-scan markers, and 70 additional markers, including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 (TGFA, D4S175, F13A1, TGFB3, D17S250, and APOC2) that have been implicated in other studies of families with orofacial clefting. LOD scores (two point and multiple point) and family-based association statistics (TDT) were calculated between each of the markers and CL/P. For the LOD score calculations, an autosomal recessive model was assumed for the inheritance of CL/P. Of the six candidate markers, significant TDT results were obtained with TGFA (P = 0.05). The most statistically significant multipoint results from the linkage genome scan were between putative genes controlling risk of CL/P and regions on chromosomes 4, 10, 12, and 15 (maximum multipoint HLOD's of 1.25, 1.30, 2.73, and 1.28 respectively). These results demonstrate the power of small numbers of families with inbred probands to detect linkage and association.
Chromosomes, Human, Pair 10↗
Genetic analysis of candidate loci in non-syndromic cleft lip families from Antioquia-Colombia and Ohio.
Non-syndromic cleft lip with or without cleft palate (CL/P) is a genetically complex birth defect, with a prevalence from 1/500 to 1/1,000 live births. Evidence from linkage and linkage disequilibrium studies is contradictory suggesting that heterogeneity between study populations may exist. A recent report of a genome widescan in 92 sib pairs from the United Kingdom revealed suggestive linkage to 10 loci [Prescott et al., 2000]. The purpose of this study is to replicate those results and evaluate additional candidate genes in 49 Colombian and 13 Ohio families. Genotypes were obtained for STRPs at 1p36, 2p13 (TGFA), 4p16 (MSX1), 6p23-25, 6q25-27, 8q23-24, 11p12-q13, 12q13, 14q24 (TGFB3), 16q22-24, 17q12-21 (RARA), and Xcen-q21. Linkage was performed using parametric (dominant and recessive models) and non-parametric (GenehunterNPL and SimIBD) analyses. In addition, heterogeneity was analyzed using GenehunterHLOD, and association determined by the TDT. The Colombian families showed significant SimIBD results for 11p12-q13 (P = 0.034), 12q13 (P = 0.015), 16q22-24 (0.01), and 17q12-21 (0.009), while the Ohio families showed significant SimIBD results for 1p36 (P = 0.02), TGFA (P = 0.005), 6p23 (P = 0.004), 11p12-q13 (P = 0.048) and significant NPL results for TGFA (NPL = 3.01, P = 0.009), 4p16 (MNPL = 2.07, P = 0.03) and 12q13 (SNPL = 3.55, P = 0.007). Significant association results were obtained only for the Colombian families in the regions 1p36 (P = 0.046), 6p23-25 (P = 0.020), and 12q13 (P = 0.046). In addition several families yielded LOD scores ranging from 1.09 to 1.73, for loci at 4p16, 6p23-25, 16q22-24, and 17q13. These results confirm previous reports for these loci. However, the differences between the two populations suggest that population specific locus heterogeneity exists. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.
Cleft Lip↗
Demographic and prenatal factors of patients with cleft lip and cleft palate. A pilot study.
BACKGROUND: Cleft lip, or CL, and cleft palate, or CP, are common congenital abnormalities. Birth prevalence ranges from one in every 500 to 1,000 in the white population and one in every 2,000 births in the African-American population. Etiologic and genetic factors contributing to CL and CP development are unknown though extensive research has been conducted. The authors conducted this pilot study to investigate a study design that could allow for an evaluation of such etiologic factors by providing the required estimate of the projected magnitude of differences between cases and controls. METHODS: The authors obtained pregnancy history data from the mothers of 137 consecutive patients at the University of Pittsburgh Cleft Palate-Craniofacial Center. The authors investigated the differences between sex or cleft status and family history of clefts, birth order, maternal age at birth and first-trimester maternal smoking and alcohol consumption. RESULTS: None of the factors showed any significant differences by sex or cleft type (P > or = .07) in the pilot data. Power estimates ranged from 12 to 71 percent. The sample size needed to obtain power of 80 percent would be 250 for variables with two categories and 480 for variables with three categories. CONCLUSIONS: There is no evidence that the factors contribute to either sex or cleft status differences. Further investigations are needed, and they should include a larger, more diverse sample of at least 250 cases, a matched control group and a focus on mothers of newborns. CLINICAL IMPLICATIONS: This study lays the groundwork for a better understanding of the etiology of CL and CP-common birth defects that present challenges for long-term dental management.
Alcohol Drinking↗
Parental evaluation of informing interviews for cleft lip and/or palate.
OBJECTIVE: This study was conducted to record subjective information concerning parental experiences and preferences with regard to informing interviews for cleft lip and/or palate. The analysis of these data was intended to help informants improve the way in which such conversations are conducted. METHODS: The study used a self-administered questionnaire. Study participants were the biological parents of children who had cleft lip and/or palate and were seen in the University of Pittsburgh Cleft Palate-Craniofacial Center. RESULTS: Results revealed that parents wanted informing health professionals to be in greater control of the informing conversation, to show more caring and confidence, to show more of their own feelings, to give parents more of an opportunity to talk and show feelings, to make a greater effort to comfort parents, to provide more information, to initiate more of a discussion about the association between clefts and mental retardation/learning disabilities, and to provide more referrals to other parents during the informing interview. A positive association between the degree to which parents reported knowing the health professionals and reported satisfaction was identified for 10 dimensions of health professional behavior. CONCLUSIONS: Parents are dissatisfied with several aspects of informing interviews for cleft lip and/or palate. The results of this study suggest ways to improve informing interviews for oral-facial clefts and other congenital anomalies.
Cleft Lip↗
Chromosome 17: gene mapping studies of cleft lip with or without cleft palate in Chinese families.
OBJECTIVE: Involvement of loci on chromosome 17, including retinoic acid receptor alpha (RARA) in nonsyndromic oral clefts has been reported in Caucasian populations, although never investigated in Asian populations. The purpose of the present study was to investigate several loci on chromosome 17, including RARA, in Chinese families. PARTICIPANTS: Thirty-six multiplex families (310 individuals), ascertained through nonsyndromic cleft lip with or without cleft palate surgical probands from hospitals in Shanghai, China, participated in the present study. There were 23 families whose probands had cleft lip and cleft palate (CLP) and 13 with cleft lip alone (CL). RESULTS: Seventeen markers, spanning chromosome 17 and about 10 cM apart were assessed. Logarithm of odds ratio (LOD) scores (two point and multipoint), model-free linkage analyses, and allelic association tests (transmission/disequilibrium, Fisher's exact tests, and chi-square) were performed on the total family sample, families with CLP probands (CLP subgroup), and families with CL probands (CL subgroup). LOD scores from the two-point analyses were inconclusive. Multipoint analyses rejected linkage except for a few regions in the CL subgroup. However, positive results were found using the model-free linkage and association methods (p < .05). The markers with positive results varied across the CL and CLP subgroups. However, the RARA region and loci nearby yielded consistently positive results. CONCLUSION: Genetic variation within the RARA locus or nearby appears to be involved in the pathogenesis of nonsyndromic oral clefts in this population. Furthermore, based on the differing pattern of results in the CL versus CLP subgroups, it appears that the formation of CL and CLP is because of either differing alleles at the same genetic locus or different but related (and/or linked) genes that modify the severity and expression of oral clefting.
Alleles↗
Perceived social support of mothers of children with clefts.
OBJECTIVE: To identify factors that may predict perceived social support in mothers of children with clefts. DESIGN: A comparison was conducted from a sample of mothers of children with oral clefts identified from a single institution (multidisciplinary craniofacial clinic). The Interpersonal Support Evaluation List and Beck Depression Inventory were completed by all participants. RESULTS: Mothers of children with visible clefts were more likely to report higher perceived social support than mothers of children with clefts that were not visible (p =.005). Mothers of female children reported higher levels of perceived social support than mothers of male children (p =.02). Mothers who had completed more years of education reported significantly higher levels of perceived social support than mothers who had completed fewer years of school (p =.03). Mothers with more children were more likely to report lower levels of perceived social support (p =.009). Maternal depression was highly correlated with perceived social support (p <.0001). CONCLUSIONS: Cleft visibility, family size, child sex, and maternal education level were important factors in predicting perceived social support in mothers of children with clefts. Child age, syndrome status, and cleft family history were not significant predictors.
Adolescent↗
Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families.
Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly. Birth prevalences range from 1/500 to 1/1,000 and are consistently higher in Asian populations than in populations of European descent. Therefore, it is of interest to determine whether the CL/P etiological factors in Asian populations differ from those in white populations. A sample of 36 multiplex families were ascertained through probands with CL/P who were from Shanghai. This is the first reported genome-scan study of CL/P in any Asian population. Genotyping of Weber Screening Set 9 (387 short tandem-repeat polymorphisms with average spacing approximately 9 cM [range 1-19 cM]) was performed by the Mammalian Genotyping Service of Marshfield Laboratory. Presented here are the results for the 366 autosomal markers. Linkage between each marker and CL/P was assessed by two-point and multipoint LOD scores, as well as with multipoint heterogeneity LOD scores (HLODs) plus model-free identity-by-descent statistics and the multipoint NPL statistic. In addition, association was assessed via the transmission/disequilibrium test. LOD-score and HLOD calculations were performed under a range of models of inheritance of CL/P. The following regions had positive multipoint results (HLOD > or =1.0 and/or NPL P< or =.05): chromosomes 1 (90-110 cM), 2 (220-250 cM), 3 (130-150 cM), 4 (140-170 cM), 6 (70-100 cM), 18 (110 cM), and 21 (30-50 cM). The most significant multipoint linkage results (HLOD > or =2.0; alpha=0.37) were for chromosomes 3q and 4q. Associations with P< or =.05 were found for loci on chromosomes 3, 5-7, 9, 11, 12, 16, 20, and 21. The most significant association result (P=.009) was found with D16S769 (51 cM).
China↗