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PubMed1987

Cleft lip with or without cleft palate: identification of sporadic cases with a high level of genetic predisposition.

Previous studies have suggested that asymmetry for certain bilaterally represented features may be an indicator of genetic predisposition to cleft lip with or without cleft palate and may therefore be of value in the individual assessment of recurrence risk, particularly for sporadic cases. An asymmetry score has been devised that may be of use in identifying those with a high level of genetic predisposition. Stepwise logistic regression selected nine variables that together correctly classified 85% of familial cleft patients and unrelated non-cleft controls. Applying the same regression equation to sporadic cases, 26% fell into the range occupied by the majority of familial patients, suggesting that these had a high level of genetic predisposition.

Adolescent↗
PubMedDate not supplied

Complex segregation analysis in a sample of consecutive newborns with cleft lip with or without cleft palate in Italy.

The mode of inheritance of cleft lip with or without cleft palate (CL/P) has been extensively investigated, but the results are controversial. We report results of complex segregation analysis performed in the families of 636 consecutive newborns with CL/P registered in the northeast Italy and Emilia Romagna congenital malformation registries to test hypotheses regarding CL/P inheritance. The programs POINTER and COMDS have been used. POINTER could not distinguish between alternative genetic models, and only the hypothesis of no familial transmission could be rejected. COMDS results, after inclusion of the severity parameter, rejected the hypotheses of a single major locus and were consistent with the two-locus model with a major dominant locus and at least one modifier locus.

Cleft Lip↗
PubMed1994

Transforming growth factor alpha: a modifying locus for nonsyndromic cleft lip with or without cleft palate?

Most (but not all) studies have found weak but significant association between restriction fragment length polymorphisms at the transforming growth factor alpha (TGFA) locus on chromosome 2p13 and nonsyndromic cleft lip with or without cleft palate (CL +/- P). However, all attempts to demonstrate genetic linkage between TGFA and CL +/- P in families have produced consistently negative lod scores which provide evidence against linkage. We typed a 3-allele single-strand conformation polymorphism at TGFA in 14 extended families with multiple CL +/- P members from West Bengal, India. No significant TGFA differences were observed between the entire sample of 34 affected people and a sample of 38 unaffected people unrelated to each other (p = 0.39). However, affected individuals with CL only showed significant differences from unaffected individuals (p = 0.008). More interestingly, the CL only and CL+P groups of individuals differed strongly from each other in their TGFA frequencies (p = 0.0002). Using an autosomal dominant model with reduced penetrance for the inheritance of a major CL +/- P locus (suggested by our prior segregation analyses), a non-significant maximum lod score of 0.13 at a recombination frequency of 20% was obtained. We suggest that the TGFA locus only modifies expression (severity) of the CL +/- P trait, which is controlled by a major (necessary) locus elsewhere; this could explain the difficulty in obtaining positive linkage results.

Alleles↗
PubMed2005

Dermatoglyphic fingerprint heterogeneity among individuals with nonsyndromic cleft lip with or without cleft palate and their unaffected relatives in China and the Philippines.

Cleft lip with or without cleft palate (CL/P) is a common birth defect (birth prevalence ranging from 1/500 to 1/2,000) with a complex etiology. Traits potentially related to CL/P, such as dermatoglyphics, may reflect the genetic and epidemiologic heterogeneity observed in CL/P. Such phenotypic heterogeneity in dermatoglyphic patterns may account for some of the variability in previously reported associations of dermatoglyphics and CL/P. To test this hypothesis, we took dermatoglyphic prints from individuals with nonsyndromic CL/P (n = 460) and their unaffected relatives (n = 254) from the Philippines and China. For both samples three raters designated the patterns as arch, ulnar loop, radial loop, whorl, or "other." Chi-square analysis and standard ANOVA were used to investigate heterogeneity between Filipino and Chinese study subjects. The significant associations between particular pattern types and CL/P were not the same in both populations, demonstrating population-specific association of CL/P and dermatoglyphic pattern types. The ANOVA of pattern type included both CL/P cases and their relatives, with affection status, sex, and population group as variables. For each pattern type except arches, population was significant (p < 0.0001); for radial loops, affection status was additionally significant (p < 0.0001). When only CL/P cases were considered, population was again significant for the ulnar loop (p < 0.0001), whorl (p < 0.0001), and "other" (p = 0.0002) patterns. The ANOVAs demonstrate between-population heterogeneity in dermatoglyphic pattern types. These results support our hypothesis that population-specific associations and population heterogeneity in dermatoglyphic patterns exist for CL/P cases and their relatives.

Analysis of Variance↗
PubMed2005

Dermatoglyphic pattern types in subjects with nonsyndromic cleft lip with or without cleft palate (CL/P) and their unaffected relatives in the Philippines.

OBJECTIVE: To investigate dermatoglyphic patterns in 95 nonsyndromic Filipino subjects with nonsyndromic cleft lip with or without cleft palate (CL/P) and 90 of their unaffected relatives. DESIGN: Retrospective study of dermatoglyphic pattern types. SETTING: Negros Occidental and Cavite in the Philippines. PARTICIPANTS: Nonsyndromic subjects with CL/P and their unaffected relatives. METHODS: Dermatoglyphic patterns were categorized as arch, ulnar loop, radial loop, whorl, or other by three independent raters. Pattern data from the subjects, the unaffected relatives, and an unaffected control population (from the literature) were compared using chi-square tests. As a measure of asymmetry, dissimilarity between pattern types on homologous fingers was quantified and compared using Student's t tests. RESULTS: The frequency of arches (p = .016) and ulnar loops (p = .04) were significantly increased, and whorls decreased in the affected group (p = .0015), compared with the unaffected group. Affected female subjects had significantly more ulnar loops and arches (p = .009 and p = .023, respectively) and fewer whorls (p < .0001) than the unaffected female subjects. There were no significant differences between affected and unaffected male subjects. Dissimilarity scores were significantly different between male and female subjects and between subjects with CL/P and unaffected relatives. Additionally, pattern type frequencies for the relatives fell in between the frequencies for the CL/P group and the controls. CONCLUSIONS: In this Filipino population, differences in frequency of dermatoglyphic pattern types and pattern dissimilarity exist between individuals with orofacial clefts and their unaffected relatives and between both groups and controls, with the major effect seen in female subjects.

Case-Control Studies↗
PubMed1998

Cleft lip with or without cleft palate: effect of family history on reproductive planning, surgical timing, and parental stress.

OBJECTIVE: This study tested whether the presence of a family history of nonsyndromic cleft lip with or without cleft palate (NSCLP) lessens the negative impact on reproductive planning, decreases treatment anxiety, and relieves parental stress when there is a recurrent cleft. DESIGN: Sixty-one participating families, retrospectively ascertained through their children with NSCLP, were divided into two groups: those with a family history of clefting and those in which only the proband was affected. SETTING: Each family completed a questionnaire either at their home or during a clinic visit. PARTICIPANTS: Questionnaires were distributed to 117 families with an NSCLP child. Of these 117, 49 (42%) had another family member with NSCLP and 68 (58%) had no prior history of clefting. Sixty-one (52%) families returned the questionnaire and were categorized by family history. MAIN OUTCOME MEASURES: The Parenting Stress Index and the Hollingshead Index of Social Position were included with family and medical history questions in the 137-item questionnaire. RESULTS: The reproductive plans of the two groups were quite similar and were not dependent on the families' actual or perceived recurrence risks of NSCLP. The majority (85%) of the children with NSCLP underwent surgical closure at the recommended age. The two groups did not significantly differ on any score on the Parenting Stress Index, indicating a similar parental stress level between the groups. CONCLUSIONS: These findings suggest that family history does not significantly influence reproductive plans, timing of cleft repair, or stress of parents of a child with NSCLP. Further, these results indicate a need for additional psychosocial study of this population.

Adolescent↗
PubMed2000

Descriptive epidemiology of nonsyndromic cleft lip with or without cleft palate in Shanghai, China, from 1980 to 1989.

OBJECTIVE: The purpose of this study was to characterize nonsyndromic cleft lip with or without cleft palate (CL+/- CP) in an Asian population. DESIGN: Birth prevalence was assessed in a large birth series in Shanghai, China. A 1:3 sex-age-hospital matched case-control design was used to assess the effects of parental ages and pregnancy history on risk of CL+/- CP. PARTICIPANTS: Records of live births from 1980 to 1989 in 22 hospitals in Shanghai, China, were reviewed, comprising 541,504 consecutive births, which is by far the largest such Chinese sample ever investigated. The case-control study included 528 (308 male, 220 female) nonsyndromic CL+/- CP cases and 1,563 (912 male, 651 female) controls. RESULTS: From 1980 to 1989, the overall birth prevalence was 1.2 per 1,000 live births with statistically significant seasonal variation (more CL+/- CP births in January to July). The overall male:female ratio was 1.40:1. For males, statistically significant associations were identified with maternal age for the most severe clefts (bilateral overall, and also bilateral CL+CP subgroup). For females, statistically significant association was shown for pregnancy age with birth order (overall and in most subgroups). CONCLUSIONS: The birth prevalence of CL+/- CP in this Asian population was similar to published Caucasian rates. The observed seasonal variation would be consistent with possible environmental factors. Significant associations with maternal age, pregnancy age, and birth order warrant additional study of pregnancy history in Asian CL+/- CP.

Birth Order↗
PubMed2002

Nonsyndromic cleft lip with or without cleft palate in China: assessment of candidate regions.

OBJECTIVE: Although Asians have the highest birth prevalence of oral-facial clefts, the majority of gene mapping studies of cleft lip with or without cleft palate (CL/P) have been in European or American Caucasians. Therefore, the objective of this study of Chinese families was to evaluate linkage and association between CL/P and 10 genetic markers in five chromosomal regions that have shown positive results in Caucasians. SETTING: Families were ascertained through nonsyndromic CL/P surgical probands from hospitals throughout Shanghai, China. PARTICIPANTS: Study participants included 671 individuals from 60 families with two or more members affected with oral-facial clefts. Of the 671 total individuals, 145 were affected. RESULTS: Ten markers from chromosomes 2, 4, 6, 17, and 19 were assessed (TGFA, MSX1, D4S194, D4S175, F13A1, GATA185H, D17S250, D17S579, D19S49, APOC2). LOD scores were calculated between each of the 10 markers and CL/P as well as model-free statistics of linkage (SimIBD) and association (TDT). None of the markers showed significantly positive LOD scores with CL/P. A significantly positive result (p =.01) was seen using SimIBD for APOC2 on chromosome 19, and a positive TDT result (p =.004) was obtained for D19S49, near APOC2. CONCLUSIONS: This is the first gene mapping study of CL/P in China. These results indicate that most of the genetic regions with positive results in Caucasian families may not be involved in CL/P found in China, although there is some positive evidence for the candidate region on chromosome 19.

Alleles↗
PubMed2003

Birth weight and gestational age of newborns with cleft lip with or without cleft palate and with isolated cleft palate.

The birth weight and gestational age of 1368 newborns with isolated cleft lip with or without cleft palate and 582 with isolated cleft palate were compared to those of matched healthy controls. The results indicate that fetuses with oral clefts are at elevated risk of having low and very low birth weight, but not of having a premature birth. Speculations on a relationship between these findings and the presence of oral clefts are presented.

Adult↗
PubMed1999

Relationship between genetic anomalies of different levels and deviations in dermatoglyphic traits. Part 6: Dermatoglyphic peculiarities of males and females with cleft lip (with or without cleft palate) and cleft palate--family study.

The present study was carried out to evaluate the effect of polygenic morbidity with respect to Cleft Palate and Cleft Lip with or without Cleft Palate (CL) in males and females based on dermatoglyphic traits (DT) and indices of intraindividual diversity (Div), fluctuating (FA) and directional (DA) asymmetry. The main objectives of the present study were as follows: a) to find DT and FA indices, which could be "marker" traits and could indicate the degree of developmental instability of the organism; b) to explore the possibility of using DT, FA, Div and DA indices of CL patients and their parents and to predict the likelihood of the disease appearing in the offsprings of apparently healthy individuals. The samples were of 106 CL patients (59 males and 47 females) and 156 of their parents (67 fathers and 89 mothers), all Israeli Jews. The prints were collected in the Beilinson (Petah-Tikva) and Rambam (Haifa) and Hadassah (Mount Scopus, Jerusalem) Hospitals, or in the abodes of the CL patients. The results were compared with the control group of healthy women and men whose data are detailed in our previous publication. Interpretation of the prints were done according to the methods and included identification of patterns, ridge counts and the measurements of distances and angles in the palms, 79 DT for every individual, 28 continuous traits, 9 discrete traits, 11 indices of Div, 15 DA indices and 16 FA indices. In CL groups increased FA indices values were found and a decreased sexual dimorphism in DT of the CL and parental groups as compared to the control--this both in terms of the number of significant differences, as well as in values of the traits (e.g. smaller differences between the male and female values). The above mentioned findings were partly confirmed also by the discriminant analysis. The values of DT parents were generally similar to those of the control. The best discrimination was obtained between the CL and control groups (70.44% between CL males and control males and 83.47% between CL females and control females). Over 50% of the DT variables were found to be suitable for including into the discriminant function.

Adolescent↗
PubMed2000

[Familial recurrence of non syndromic cleft lip with or without cleft palate in Chilean populations].

BACKGROUND: The presence of major genes in the susceptibility of non syndromic cleft lip with or without cleft palate (CL/P) in Chile has been postulated, considering the high prevalence and familial aggregation of this condition. AIM: To study the familial recurrence of CL/P in Chile. PATIENTS AND METHODS: The recurrence risk of CL/P was studied in 217 extended pedigrees where 33 (15.2%) were multiplex (21 male and 12 female propositi). These multiplex extended pedigrees (with more than one affected individual) represented 75 nuclear pedigrees, constituted by 840 males and 803 females and are the basic information of this study. RESULTS: A significantly higher frequency of affected males (4.15%) than affected females (2.27%) was observed, independent of the difference in number of propositi by sex. Even though no differences were observed between families where both parents were unaffected, compared to those with only one affected parent, a higher proportion of affected descendants was found when the affected propositi was the mother. In multiplex families, the recurrence risk, according to the genetic proximity to the proband, was 10.1, 3.6 and 3.3% respectively for first, second and third degree relatives. The figures were 1.5, 0.5 and 0.4% respectively, when adjusted to the 217 extended pedigrees. Considering that the risk for the general population in Chile is approximately 0.16%, it is 10.3, 3.2 and 2.6 times higher among affected families. CONCLUSIONS: The high heritability of CL/P and the risk encountered for the Chilean population supports the hypothesis of major genes involved in its susceptibility.

Chile↗
PubMed2000

Evaluation of prenatal diagnosis of cleft lip with or without cleft palate and cleft palate by ultrasound: experience from 20 European registries. EUROSCAN study group.

Ultrasound scans in the mid-trimester of pregnancy are now a routine part of antenatal care in most European countries. Using data from registries of congenital anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of cleft lip with or without cleft palate (CL(P)) and cleft palate (CP). All CL(P) and CPs suspected prenatally and identified at birth in the period 1996-98 were registered from 20 Congenital Malformation Registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK, Ukraine. These registries followed the same methodology. A total of 709,027 births were covered; 7758 cases with congenital malformations were registered. Included in the study were 751 cases reported with facial clefts: 553 CL(P) and 198 CP. The prenatal diagnosis by transabdominal ultrasound of CL(P) was made in 65/366 cases with an isolated malformation, in 32/62 cases with chromosomal anomaly, in 30/89 cases with multiple malformations and in 21/36 syndromic cases. The prenatal diagnosis of CP was made in 13/198 cases. One hundred pregnancies were terminated (13%); in 97 of these the cleft was associated with other malformations.

Cleft Lip↗
PubMed1992

Cleft lip with or without cleft palate in Shanghai, China: evidence for an autosomal major locus.

Orientals are at higher risk for cleft lip with or without cleft palate (CL +/- P) than Caucasians or blacks. We collected demographic and family data to study factors contributing to the etiology of CL +/- P in Shanghai. The birth incidence of nonsyndromic CL +/- P (Shanghai 1980-87) was 1.11/1,000, with a male/female ratio of 1.42. Almost 2,000 nonsyndromic CL +/- P probands were ascertained from individuals operated on during the years 1956-83 at surgical hospitals in Shanghai. Detailed family histories and medical examinations were obtained for the probands and all available family members. Genetic analyses of the probands' families were performed under the mixed model with major locus (ML) and multifactorial (MFT) components. The hypotheses of no familial transmission and of MFT alone could be rejected. Of the ML models, the autosomal recessive was significantly most likely and was assumed for testing three complex hypotheses: (1) ML and sporadics; (2) ML and MFT; (3) ML, MFT, and sporadics. None of the complex models were more likely than the ML alone model. In conclusion, the best-fitting, most parsimonious model for CL +/- P in Shanghai was that of an autosomal recessive major locus.

Asian People↗
PubMed1992

Familial recurrence-pattern analysis of cleft lip with or without cleft palate.

Cleft lip with or without cleft palate (CL/P) is a common congenital malformation with an incidence in European white populations of about 1/1,000. The familial clustering of CL/P has been extensively characterized, and epidemiological studies have proposed monogenic models (with reduced penetrance), multifactorial/threshold models, and mixed major-gene/multifactorial models to explain its inheritance. The recognition of an association between two RFLPs at the transforming growth factor alpha (TGFA) locus and CL/P supports a major-gene component to the etiology of CL/P. Risch has shown that the recurrence risk ratio lambda R (risk to relatives, vs. population prevalence) is a useful pointer to the mode of inheritance. Here we further develop the use of lambda R to analyze recurrence-risk data for CL/P. Recurrence risks for first-, second-, and third-degree relatives equate well with oligogenic models with as few as four loci. A monogenic/additive model is strongly rejected. The limited available twin data are also consistent with this model. A "major gene" interacting epistatically with an oligogenic background is shown to be a plausible alternative. Power calculations for a linkage study to map the CL/P major-risk locus suggest that a sample of 50 affected sib pairs will be adequate, but linkage to minor-risk loci will require very much larger samples.

Chromosome Mapping↗
PubMed1992

Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci.

The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus. This finding has since been replicated, in whole or in part, in three independent studies. Here we extend our original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls. The other candidate genes were the retinoic acid receptor (RARA), the bcl-2 oncogene, and the homeobox genes 2F, 2G, and EN2. Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance. Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing). The effect on risk of the A2 allele appears to be additive, and although the A2A2 homozygote only has an odds ratio of about 2 and recurrence risk to first-degree relatives (lambda 1) of 1.06, because it is so common it may account for as much as a third of the attributable risk of clefting. There is no evidence of interaction between the TGFA and RARA polymorphisms on risk, and jointly they appear to account for almost half the attributable risk of clefting.

Blotting, Southern↗
PubMed1992

Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis.

Nonsyndromic cleft lip with or without cleft palate (CL +/- P) is traditionally recognized as a multifactorial threshold trait (MFT). Recently, however, evidence for the involvement of a major gene in the etiology of CL +/- P has been reported. To assess the potential for major-gene involvement in the etiology of this trait, familial recurrence patterns from several family studies of CL +/- P were reanalyzed. The recurrence patterns in first-degree relatives of CL +/- P probands were found to be compatible with the expectations for either an MFT or a generalized single-major-locus (gSML) trait. The use of multiple thresholds based on proband sex, defect bilaterality, or palatal involvement did not help to discriminate between these models. However, the pattern of recurrence among MZ twins and more remote relatives of CL +/- P probands is not consistent with gSML inheritance but is compatible with either an MFT model or a model specifying multiple interacting loci. For such a model, no single locus can account for more than a sixfold increase in risk to first-degree relatives. These findings have important implications with regard to the feasibility of detecting linkage to loci conferring susceptibility to CL +/- P.

Cleft Lip↗
PubMed2006

[Study on the association between transforming growth factor alpha gene TaqI variant and cleft lip with or without cleft palate].

OBJECTIVE: To study the association between transforming growth factor alpha gene (TGFalpha) TaqI variant and nonsyndromic cleft lip with or without cleft palate (nsCL/P) in Chinese population. METHODS: TGFalpha TaqI variant was detected using polymerase chain reaction-restriction fragment length polymorphism for DNA samples of the 149 triads with nsCL/P affected child. We performed the Transmission/disequilibrium test and the family-based association study (FBAT) to identify the associations between this variant and risk of nsCL/P. RESULTS: Significant distortion of C2 allele at TGFalpha TaqI locus in nsCL/P groups (P > 0.05) was not found. In the family-based association test, C2 allele and offspring C2C1 genotype was not found to be significantly associated with an increase risk of nsCL/P (P > 0.05). CONCLUSION: Our findings did not suggest an association between offspring TGFalpha TaqI variant and the increased risk of nsCL/P in Chinese population.

Child↗
PubMed1986

Major gene determination of liability to cleft lip with or without cleft palate: a multiracial view.

Despite nearly half a century of intensive investigation, the etiology of non-syndromic cleft lip with or without cleft palate (CL +/- P) remains unknown because most studies have been descriptive rather than analytic. This study summarizes rigorous analyses of CL +/- P in the families of non-syndromic, CL +/- P surgical probands from three populations: Denmark, London, England, and Shanghai, China. Three main conclusions could be drawn from the results. The data provide no support for the multifactorial threshold model summarized by Carter (1976) and most often proposed to explain the etiology of CL +/- P. Each dataset provides evidence that there may be a major gene for liability to CL +/- P in at least a portion of cases. The data are consistent with possible genetic heterogeneity in CL +/- P.

China↗