Biomedical subjects

P A Romitti

Publications and source records attributed to P A Romitti.

13 recordsLinked to original sources

PubMed2006

Genetic evidence for the role of loci at 19q13 in cleft lip and palate.

BACKGROUND: Clefts of the lip and palate are common birth defects, affecting approximately 1 in 700 births worldwide. The aetiology of clefting is complex, with multiple genetic and environmental influences. METHODS: Genotype based linkage disequilibrium analysis was conducted using the family based association test (FBAT) and the likelihood ratio test (LRT). We also carried out direct sequencing of the PVR and PVRL2 candidate genes based on their homology to PVRL1, a gene shown previously to cause Margarita Island clefting. Participants included 434 patients with cleft lip with or without cleft palate or cleft palate only and their mothers from eight countries in South America, 205 nuclear triads (father-mother-affected child) from Iowa, 541 nuclear triads from Denmark, and 100 patients with cleft lip and palate from the Philippines. RESULTS: An allelic variant in the PVR gene showed statistically significant association with both South American and Iowa populations (p = 0.0007 and p = 0.0009, respectively). Direct sequencing of PVR and PVRL2 yielded 26 variants, including two rare amino acid changes, one in each gene, which were not seen in controls. CONCLUSIONS: We found an association between a common variant in a gene at 19q and isolated clefting in two heterogeneous populations. However, it is unclear from our data if rare variants in PVR and PVRL2 are sufficient to cause clefting in isolation.

Alleles↗

PubMed2003

Inheritance of cleft palate in South America: evidence for a major locus recessive.

OBJECTIVES: Determine the model of inheritance of non-syndromic cleft palate in humans. DESIGN: Complex segregation analysis performed in families of consecutive newborns affected with non-syndromic cleft palate. SETTING AND SAMPLE POPULATION: The Latin American Collaborative Study of Congenital Malformations (ECLAMC). Four hundred and seven consecutive newborns affected with non-syndromic cleft palate registered during the period 1967-97. OUTCOME MEASURE: Likelihood ratio test and Akaike information criterion (AIC) values. RESULTS: The single major locus recessive model provided a significantly better explanation of the data. It was the most parsimonious and had the smallest AIC value of the six models tested with approximately the same likelihood as the general model (chi2 = 2.44, p = 0.5). CONCLUSIONS: To have defined a genetic model for non-syndromic cleft palate and provided evidence for a single major locus inheritance suggests that genetic linkage studies could be implemented.

Cleft Palate↗

PubMed2003

Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate.

MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.

Amino Acid Sequence↗

PubMed2001

The National Birth Defects Prevention Study.

The National Birth Defects Prevention Study was designed to identify infants with major birth defects and evaluate genetic and environmental factors associated with the occurrence of birth defects. The ongoing case-control study covers an annual birth population of 482,000 and includes cases identified from birth defect surveillance registries in eight states. Infants used as controls are randomly selected from birth certificates or birth hospital records. Mothers of case and control infants are interviewed and parents are asked to collect buccal cells from themselves and their infants for DNA testing. Information gathered from the interviews and the DNA specimens will be used to study independent genetic and environmental factors and gene-environment interactions for a broad range of birth defects. As of December 2000, 7,470 cases and 3,821 controls had been ascertained in the eight states. Interviews had been completed with 70% of the eligible case and control mothers, buccal cell collection had begun in all of the study sites, and researchers were developing analysis plans for the compiled data. This study is the largest and broadest collaborative effort ever conducted among the nation's leading birth defect researchers. The unprecedented statistical power that will result from this study will enable scientists to study the epidemiology of some rare birth defects for the first time. The compiled interview data and banked DNA of approximately 35 categories of birth defects will facilitate future research as new hypotheses and improved technologies emerge.

Case-Control Studies↗

PubMed2000

Acceptability of telepsychiatry to a rural population.

Sixty-seven residents of a rural Midwestern state were surveyed by telephone to determine which factors influence their willingness to receive mental health services through live, two-way audio and video transmission. Two-thirds of the survey respondents were willing to participate in telepsychiatry. Many expressed reluctance, however. They were concerned about maintaining confidentiality, and they perceived telepsychiatry as impersonal. Medicare enrollees and older survey respondents were less willing than younger respondents to endorse the use of telemedicine.

Adult↗

PubMed1999

Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts.

Previous studies suggest that the relationship between genes and nonsyndromic cleft lip +/- cleft palate (CLP) or cleft palate only (CP) may be modified by the environment. Using data from a population-based case-control study, we examined allelic variants for three genes, i.e., transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), and Msh (Drosophila) homeobox homolog 1 (MSX1), and their interactions with two exposures during pregnancy (maternal cigarette smoking and alcohol consumption) as risk factors for CLP and CP. For each cleft phenotype, risk estimates associated with most allelic variants tended to be near unity. Risk estimates for maternal smoking (> or = 10 cigarettes/day) were significantly elevated for CP and were most elevated among infants with allelic variants at the TGFB3 or MSX1 sites. By comparison, risk estimates for maternal alcohol consumption (> or = 4 drinks/month) were significantly elevated for CLP and were most elevated among infants with allelic variants at the MSX1 site. Our results suggest that development of CLP and CP may be influenced independently by maternal exposures but more significantly by interaction of such exposures and specific allelic variants.

Alcohol Drinking↗

PubMed1999

Evaluation of reports of periconceptual occupational exposure: maternal-assessed versus industrial hygienist-assessed exposure.

BACKGROUND: While the number of women entering the work force has grown, so has the importance of investigating occupational reproductive hazards. The objective of this study was to examine the concordance between maternal-assessed and industrial hygienist-assessed exposure to four classes of occupational agents - video display terminals, paints, solvents, and agricultural chemicals. METHODS: Case (n=87) and control (n=102) mothers who participated in a population-based study of orofacial clefts provided occupational histories and exposure (yes/no) to selected classes of agents for the one-year period prior to their child's delivery. Two industrial hygienists reviewed the occupational histories and assigned mothers an exposure status for each class of agent. Using industrial hygienist-assessed exposure as the "gold standard", sensitivity and specificity of maternal reports were calculated for each class of agent. Kappa statistics were calculated for the study population to account for chance agreement between the two exposure assessment methods. RESULTS: Sensitivity estimates for cases were the highest for video display terminals (77%) and lowest for agricultural chemicals (14%). Respective estimates for controls were 74% and 14%. Specificity estimates tended to be high for both groups. Kappa values ranged from 0.16-0.45. CONCLUSIONS: With regard to the classes of agents examined, these data suggest screening questions alone may not be the preferred method of obtaining occupational exposure histories, even when the time period of interest is fairly short and recent.

Adult↗

PubMed1998

The effect of follow-up on limiting non-participation bias in genetic epidemiologic investigations.

The use of a comprehensive follow-up strategy to limit non-participation bias was evaluated in a population-based case-control study of orofacial clefts. Birth parents were requested to provide exposure data, and index children and parents were asked to provide blood specimens. Follow-up included telephone or postal reminders every two weeks for up to three months. Consent to participate was received from 281 (76.6%) case mothers and 246 (72.4%) case fathers. The corresponding totals for controls were 279 (54.7%) and 245 (49.8%). Evaluation of participation rates by intensity of follow-up showed that 23% of case and 18% of control families consented without reminders (first stage); 81% of cases and 83% of controls agreed following one or two reminders (second stage); and the remainder of participants consented following three or more reminders (final stage). Cumulative distributions of sociodemographic characteristics differed little between second and final stage participants. Odds ratios for maternal multivitamin use were similar between second and final stage participants, whereas those for maternal and paternal smoking tended to decline. Although follow-up measures were necessary to enroll most families, use of more than two reminders did not appear to increase the representativeness of the sample; however, termination of recruitment after only two reminders would have led to different conclusions. Future studies require data collection protocols that encourage participation from all population subgroups, and one alternative is presented.

Adult↗

PubMed1998

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.

Amino Acid Substitution↗

PubMed1997

Maternal interview reports of family history of birth defects: evaluation from a population-based case-control study of orofacial clefts.

Accurate family histories of birth defects are critical for risk assessment and etiologic investigations. Typically, information about family history of birth defects is ascertained from interviews with birth mothers of index children; however, the quality of these interviews is rarely assessed. We evaluated family history information provided by case (n = 28) and control (n = 29) mothers who participated in a population-based, case-control study of orofacial clefts. Interview responses from mothers were compared to questionnaire reports collected by mail from first- and second-degree parental relatives. A total of 345 case and 380 control adult relatives completed questionnaires. These relatives also provided reports for 130 case and 169 control offspring. To examine the quality of birth defect reports, the sensitivity and specificity of birth mother responses were calculated. Sensitivity for presence (yes/no) of a birth defect was 31% for case mothers and 9% for control mothers. Specificity for case and control mothers was 98% and 97%, respectively. Interview responses from mothers who participate in family genealogy were more likely to be concordant with relative reports than were responses from mothers who do not participate in family genealogy. Case mother responses were more likely to be concordant than control mother responses. These results suggest that reliance on interview reports from birth mothers may lead to an underestimation of the occurrence of birth defects in relatives. Future investigations should explore methods to improve the quality of informant reports about family histories of birth defects. One alternative approach is discussed.

Case-Control Studies↗

PubMed1996

Maternal alcohol use and risk of orofacial cleft birth defects.

Maternal alcohol use during pregnancy is a known cause of birth defects associated with the fetal alcohol syndrome, but its role in more common, isolated, craniofacial birth defects is not well understood. A population-based, case-control study of orofacial clefts was conducted in Iowa using births during 1987-1991. Cases were identified by the Iowa Birth Defects Registry and classified as having a cleft lip with or without cleft palate (CLP) or cleft palate only (CP) and whether the cleft was isolated or occurred with other birth defects. Controls were selected from normal Iowa births. Maternal alcohol use during pregnancy was classified according to self-reported drinks consumed per month. Results are based on 302 controls and the following numbers in each case group: 118 isolated CLP, 56 isolated CP, 51 CLP with multiple defects, and 62 CP with multiple defects. Compared to women who did not drink alcohol during pregnancy, the relative odds of isolated CLP rose with increasing level of maternal drinking as follows: 1-3 drinks per months, 1.5; 4-10 drinks per month, 3.1; more than 10 drinks per month, 4.7 (chi-square test for trend, P = 0.003). Adjustment for maternal smoking, vitamin use, education, and household income did not substantially alter these results. No significant association was found between alcohol use and isolated cleft palate or clefts in children with multiple birth defects. Alcohol use during pregnancy may be a cause of isolated cleft lip with or without cleft palate.

Adult↗

PubMed1993

Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO).

Genetic analysis and tissue-specific expression studies support a role for transforming growth-factor alpha (TGFA) in craniofacial development. Previous studies have confirmed an association of alleles for TGFA with nonsyndromic cleft lip with or without cleft palate (CL/P) in humans. We carried out a retrospective association study to determine whether specific allelic variants of the TGFA gene are also associated with cleft palate only (CPO). The PCR products from 12 overlapping sets of primers to the TGFA cDNA were examined by using single-strand conformational polymorphism analysis. Four DNA polymorphic sites for TGFA were identified in the 3' untranslated region of the TGFA gene. These variants, as well as previously identified RFLPs for TGFA, were characterized in case and control populations for CPO by using chi 2 analysis. A significant association between alleles of TGFA and CPO was identified which further supports a role for this gene as one of the genetic determinants of craniofacial development. Sequence analysis of the variants disclosed a cluster of three variable sites within 30 bp of each other in the 3' untranslated region previously associated with an antisense transcript. These studies extend the role for TGFA in craniofacial morphogenesis and support an interrelated mechanism underlying nonsyndromic forms of CL/P.

Adolescent↗

PubMedDate not supplied

Feasibility of collecting disease reports from relatives for genetic epidemiologic investigations.

Self-reports of disease from relatives are generally believed to be more detailed than those received from a family informant, although differential participation may exist among the relatives who provide information. To investigate the potential for differential participation, we requested permission to contact relatives of mothers (informants) who had provided family history information for a population-based case-control study of orofacial clefts. Birth defect and cancer self-reports were received from 345 (65.6%) case and 380 (68.8%) control relatives. Participants and nonparticipants differed little by type (maternal or paternal) or degree of relationship. Informants, however, were more likely to permit contact with relatives who were maternal, first-degree and female. Relatives appeared willing to provide self-reports, although the potential for differential selection introduced by informants should be considered.

Case-Control Studies↗