scholarly journals A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals

2018 ◽  
Author(s):  
Jenna C. Carlson ◽  
Deepti Anand ◽  
Azeez Butali ◽  
Carmen J. Buxo ◽  
Kaare Christensen ◽  
...  
Keyword(s):  
Complex Traits ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Expression Patterns ◽  
Complex Trait ◽  
Genetic Effects ◽  
Phenotypic Heterogeneity ◽  
New Associations ◽  
Orofacial Clefting ◽  
Shared Genetic

AbstractPhenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes – cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a “cleft map” of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 (CP), WNT5A (CLP)), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.

scholarly journals The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

2020 ◽  
Author(s):  
Sarah W. Curtis ◽  
Daniel Chang ◽  
Myoung Keun Lee ◽  
John R. Shaffer ◽  
Karlijne Indencleef ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Cleft Lip ◽  
Mixed Model ◽  
Cleft Lip And Palate ◽  
Phenotypic Heterogeneity ◽  
Mixed Model Approach ◽  
Genome Wide ◽  
A Genome ◽  
Model Approach

AbstractNonsyndromic orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and, like many complex traits, OFCs are phenotypically and etiologically heterogenous. The phenotypic heterogeneity of OFCs extends beyond the structures affected by the cleft (e.g., cleft lip (CL) and cleft lip and palate (CLP) to other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity. Unilateral clefts are more frequent than bilateral clefts for both CL and CLP, but the genetic architecture of these subtypes is not well understood, and it is not known if genetic variants predispose for the formation of one subtype over another. Therefore, we tested for subtype-specific genetic associations in 44 bilateral CL (BCL) cases, 434 unilateral CL (UCL) cases, 530 bilateral CLP cases (BCLP), 1123 unilateral CLP (UCLP) cases, and unrelated controls (N = 1626), using the mixed-model approach implemented in GENESIS. While no novel loci were found in subtype-specific analyses comparing cases to controls, the genetic architecture of UCL was distinct compared to BCL, with 43.8% of suggestive loci (p < 1.0×10−5) having non-overlapping confidence intervals between the two subtypes. To further understand the genetic risk factors for severity differences, we then performed a genome-wide scan for modifiers using a similar mixed-model approach and found one genome-wide significant modifier locus on 20p11 (p = 7.53×10−9), 300kb downstream of PAX1, associated with higher odds of BCL compared to UCL, which also replicated in an independent cohort (p = 0.0018) and showed no effect in BCLP (p>0.05). We further found that SNPs at this locus were associated with normal human nasal shape. Taken together, these results suggest bilateral and unilateral clefts may have differences in their genetic architecture, especially between CL and CLP. Moreover, our results suggest BCL, the rarest form of OFC, may be genetically distinct from the other OFC subtypes. This expands our understanding of genetic modifiers for subtypes of OFCs and further elucidates the genetic mechanisms behind the phenotypic heterogeneity in OFCs.

Prenatal Diagnosis of Cleft Lip and Palate

2003 ◽  
Vol 40 (2) ◽  
pp. 186-189 ◽  
Author(s):  
N. Johnson ◽  
Jonathan R. Sandy
Keyword(s):  
Prenatal Diagnosis ◽  
Early Diagnosis ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Reliability And Validity ◽  
Review Article ◽  
Ultrasound Diagnosis ◽  
Orofacial Clefting ◽  
The Impact

Objective The use of ultrasound for the prenatal diagnosis of cleft lip and palate has aided considerably in the early diagnosis of orofacial clefting. The impact and consequences of this need to be considered as the reliability and validity of ultrasound diagnosis increases. This review article considers a number of these issues as well as up-to-date information on the quality of the technique.

Genetics of cleft lip and palate revisited

2003 ◽  
Vol 27 (4) ◽  
pp. 311-320 ◽  
Author(s):  
Puneet Batra ◽  
Ritu Duggal ◽  
Hari Parkash
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Speech Therapy ◽  
Cleft Lip And Palate ◽  
Gene List ◽  
Complex Trait ◽  
Case Control Studies ◽  
Systematic Screening ◽  
Complex Interactions ◽  
Facial Development

Cleft lip with or without cleft palate (CL/CP) is one of the most common structural birth defects, with treatment including multiple surgeries, speech therapy, and dental and orthodontic treatments over the first 18 years of life. Providing care for these patients and families includes educating patients and parents about the genetics of CL/CP, as well as meeting the immediate medical needs.Attempts at identifying susceptibility loci via family and case-control studies have proved inconsistent. It is likely that initial predictions of the complex interactions involved in facial development were underestimated. The candidate gene list for CL/P is getting longer and the need for an impartial, systematic screening technique, to implicate or refute the inclusion of particular loci, is apparent. So we are faced with the question "Can this complex trait be too complex?"The aim of this review is to make the dentist aware of the differences between syndromic and non-syndromic cleft as well as understanding the etiological variation in cleft lip with and without cleft palate. This will aid the dentist in diagnosis and give proper genetic counseling to parents and patients of cleft lip and palate.

scholarly journals Malposition of Unerupted Mandibular Second Premolar in Children with Cleft Lip and Palate

2007 ◽  
Vol 77 (6) ◽  
pp. 1062-1066 ◽  
Author(s):  
Miri Shalish ◽  
Leslie A. Will ◽  
Stephen Shustermann
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Control Sample ◽  
Control Group ◽  
Control Groups ◽  
The Mean ◽  
The Difference ◽  
Inferior Border ◽  
Paired T Test ◽  
Shared Genetic

Abstract Objective: To determine whether distoangular malposition of the unerupted mandibular second premolar (MnP2) is more frequent in children with unilateral clefts of the lip and palate. Materials and Methods: This retrospective study examined panoramic radiographs from 45 patients with unilateral clefts of the lip and/or palate who had no previous orthodontics. A control sample consisted of age- and sex-matched patients. The distal angle formed between the long axis of MnP2 and the tangent to the inferior border was measured. The mean, standard deviation, and range were calculated for the angles measured in the cleft and the control groups. The significance of the differences between the means was evaluated by the paired t-test. The angles of the cleft and noncleft sides were also measured and compared. Results: The mean inclination of the MnP2 on the cleft side was 73.6°, compared with 84.6° in the control group. This difference was highly significant statistically (P &lt; .0001). The difference in angles from the cleft and noncleft sides was 0.7°, not statistically significant. A significant association was found between clefting and distoangular malposition of the developing MnP2, suggesting a shared genetic etiology. This association is independent of the clefting side, ruling out possible local mechanical effects. Conclusion: Clinicians should be aware of the potential for anomalous development of MnP2 in children with clefts.

Cleft Lip and Palate in Ectodermal Dysplasia

2020 ◽  
pp. 105566562094912
Author(s):  
Ingrid M. Ganske ◽  
Tim Irwin ◽  
Olivia Langa ◽  
Joseph Upton ◽  
Wen-Hann Tan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Ectodermal Dysplasia ◽  
Phenotypic Expression ◽  
Velopharyngeal Insufficiency ◽  
Pathogenic Variants ◽  
Orofacial Clefting ◽  
Outcomes Measures ◽  
Cleft Lip Palate ◽  
Dentofacial Orthopedics

Objective: Ectodermal dysplasia (ED) comprises multiple syndromes that affect skin, hair, nails, and teeth, and sometimes are associated with orofacial clefting. The purpose of this study is to (1) identify the prevalence and characteristics of cleft lip and/or palate (CL/P) in patients with ED and (2) describe the management and outcomes. Design: Retrospective review from 1990 to 2019. Patients: All patients with ED treated at Boston Children's Hospital. Main Outcomes Measures: Prevalence of CL/P was calculated and clinical details recorded: phenotypic anomalies, cleft type, operative treatment, and results of repair. Results: Of 170 patients with a purported diagnosis of ED, 24 (14%) had CL/P. Anatomic categories were bilateral CL/P (67%), unilateral CL/P (8%), and cleft palate only (25%). The most common ED syndrome (37%) was ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC). Pathogenic variants in TP63 were the most frequent finding in the 11 patients who had genetic testing. Aberrations from a typical clinical course included failure of presurgical dentofacial orthopedics, dehiscence of nasolabial adhesion, and total palatal absence requiring free-flap construction. Two patients had prolonged postoperative admission for respiratory infection. High fistula (8%) and velopharyngeal insufficiency (33%) rates reflected the predominance of bilateral complete forms. Conclusions: As in other types of syndromic CL/P, cleft phenotypic expression in ED is more severe than the general cleft population. Further studies are needed to correlate genotype and phenotype for the distinct syndromes included in the ED spectrum.

scholarly journals Genetic Association Studies of Cleft Lip and/or Palate with Hypodontia outside the Cleft Region

2003 ◽  
Vol 40 (3) ◽  
pp. 274-279 ◽  
Author(s):  
Rebecca L. Slayton ◽  
Laura Williams ◽  
Jeffrey C. Murray ◽  
James J. Wheeler ◽  
Andrew C. Lidral ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Candidate Genes ◽  
Cleft Lip ◽  
Transforming Growth Factor ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Polymorphism Analysis ◽  
Missing Teeth ◽  
Orofacial Clefting ◽  
Genotype Information

Objective The purpose of this study was to determine whether the candidate genes previously studied in subjects with cleft lip, cleft palate, or both are associated with hypodontia outside the region of the cleft. Subjects One hundred twenty subjects from the Iowa Craniofacial Anomalies Research Center were selected based on the availability of both dental records and genotype information. Method The type of orofacial clefting and type and location of dental anomalies (missing teeth, supernumerary teeth, or peg laterals) were assessed by dental chart review and radiographic examination. Genotype analysis of candidate genes was performed using polymerase chain reaction/single-strand conformation polymorphism analysis. Results The prevalence of hypodontia in this sample was 47.5%, with 30.0% of subjects having missing teeth outside the cleft. There was a positive association between subjects with cleft lip or cleft lip and palate who had hypodontia outside the cleft region (compared with noncleft controls) and both muscle segment homeo box homolog 1 (MSX1) (p = .029) and transforming growth factor beta 3 (TGFB3) (p = .024). It was not possible in this analysis to determine whether this association was specifically associated with orofacial clefting combined with hypodontia or whether it was due primarily to the clefting phenotype. Conclusions In this sample, there was a significantly greater incidence of hypodontia outside the cleft region in subjects with cleft lip and palate, compared with cleft lip only or cleft palate only. Cleft lip and/or palate with hypodontia outside the cleft region was positively associated with both TGFB3 and MSX1, compared with noncleft controls.

Cleft Lip and Palate in Jordan: Birth Prevalence Rate

2004 ◽  
Vol 41 (6) ◽  
pp. 609-612 ◽  
Author(s):  
F. Al Omari ◽  
I. K. Al-Omari
Keyword(s):  
Prevalence Rate ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Prevalence Rates ◽  
Orofacial Clefts ◽  
Oral Clefts ◽  
Birth Prevalence ◽  
Live Births ◽  
Orofacial Clefting ◽  
Retrospective Investigation

Objective and Design A retrospective investigation was conducted to determine the prevalence rate of Jordanian children born with oral clefts from 1991 to 2001. Setting Hospital surgical records from two main sources were used to identify all children born with orofacial clefting. Information about date of birth, sex, cleft types, and associated major anomalies and syndromes were recorded. Results The overall prevalence rate for live births with cleft lip, cleft palate, or both was 1.39 per 1000 live births. Thirty percent of the clefts identified affected the lip, 22 percent affected the palate, and 48 percent involved the clefts of the lip and palate. In general, higher prevalence rates were found for boys than girls (55% boys versus 45% girls). There was a statistically significant sex difference between the cleft types. Clefts of the isolated palate, however, were more common in girls. Eighteen percent of patients with cleft were associated with major anomalies or syndromes. Conclusions The reported prevalence rate for orofacial clefts among Jordanians is similar to the previously reported prevalence rate in white Caucasians. Results and future recommendations are discussed.

scholarly journals Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

2006 ◽  
Vol 43 (1) ◽  
pp. 21-29 ◽  
Author(s):  
M. A. Mansilla ◽  
M. E. Cooper ◽  
T. Goldstein ◽  
E. E. Castilla ◽  
J. S. Lopez Camelo ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Missense Mutations ◽  
Nucleotide Polymorphisms ◽  
Normal Variants ◽  
Specific Sequence ◽  
Orofacial Clefting

Objective Mutations in patched (PTCH) cause the nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome. Nevoid basal cell carcinoma syndrome may present with developmental anomalies, including rib and craniofacial abnormalities, and predisposes to several tumor types, including basal cell carcinoma and medulloblastoma. Cleft palate is found in 4% of individuals with nevoid basal cell carcinoma syndrome. Because there might be specific sequence alterations in PTCH that limit expression to orofacial clefting, a genetic study of PTCH was undertaken in cases with cleft lip and/or palate (CL/P) known not to have nevoid basal cell carcinoma syndrome. Results Seven new normal variants spread along the entire gene and three missense mutations were found among cases with cleft lip and/or palate. One of these variants (P295S) was not found in any of 1188 control samples. A second variant was found in a case and also in 1 of 1119 controls. The third missense (S827G) was found in 5 of 1369 cases and in 5 of 1104 controls and is likely a rare normal variant. Linkage and linkage desequilibrium also was assessed using normal variants in and adjacent to the PTCH gene in 220 families (1776 individuals), each with two or more individuals with isolated clefting. Although no statistically significant evidence of linkage (multipoint HLOD peak = 2.36) was uncovered, there was borderline evidence of significant transmission distortion for one haplotype of two single nucleotide polymorphisms located within the PTCH gene (p = .08). Conclusion Missense mutations in PTCH may be rare causes of isolated cleft lip and/or palate. An as yet unidentified variant near PTCH may act as a modifier of cleft lip and/or palate.

scholarly journals Quantifying the contribution of dominance effects to complex trait variation in biobank-scale data

2020 ◽  
Author(s):  
Ali Pazokitoroudi ◽  
Alec M. Chiu ◽  
Kathryn S. Burch ◽  
Bogdan Pasaniuc ◽  
Sriram Sankararaman
Keyword(s):  
Complex Traits ◽  
Complex Trait ◽  
Genetic Effects ◽  
Trait Variation ◽  
Wide Range ◽  
Unbiased Estimates ◽  
The Uk ◽  
Additive Genetic Effects ◽  
Intense Debate ◽  
Scale Data

AbstractThe proportion of variation in complex traits that can be attributed to non-additive genetic effects has been a topic of intense debate. The availability of Biobank-scale datasets of genotype and trait data from unrelated individuals opens up the possibility of obtaining precise estimates of the contribution of non-additive genetic effects. We present an efficient method that can partition the variation in complex traits into variance that can be attributed to additive (additive heritability) and dominance (dominance heritability) effects across all genotyped SNPs in a large collection of unrelated individuals. Over a wide range of genetic architectures, our method yields unbiased estimates of heritability. We applied our method, in turn, to array genotypes as well as imputed genotypes (at common SNPs with minor allele frequency, MAF > 1%) and 50 quantitative traits measured in 291, 273 unrelated white British individuals in the UK Biobank. Averaged across these 50 traits, we find that additive heritability on array SNPs is 21.86% while dominance heritability is 0.13% (about 0.48% of the additive heritability) with qualitatively similar results for imputed genotypes. We find no evidence for dominance heritability ( accounting for the number of traits tested) and estimate that dominance heritability is unlikely to exceed 1% for the traits analyzed. Our analyses indicate a limited contribution of dominance heritability to complex trait variation.

Cleft Lip and Palate: Association with Other Congenital Malformations

2009 ◽  
Vol 33 (3) ◽  
pp. 207-210 ◽  
Author(s):  
Soraya Beriaghi ◽  
Sandra Myers ◽  
Scott Jensen ◽  
Shanti Kaimal ◽  
Cynthia Chan ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Congenital Malformations ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Diagnostic Testing ◽  
Research Hospital ◽  
Orofacial Clefting ◽  
Orofacial Region ◽  
Associated Malformations ◽  
Hospital Study

Orofacial clefts are frequently associated with other congenital malformations. Studies vary in incidence and types of anomalies. Objective: To evaluate associated malformations in orofacial cleft patients at a major research hospital. Study Design: Medical records of 1127 patients, in the Cleft Palate / Craniofacial Clinic, Boys Town National Research Hospital, from January 1980 through February 2000 were reviewed. Patients were divided into two categories: 1) cleft palate only (CP), and 2) cleft lip, with or without cleft palate (CL±P). Further categorization included location and type, if any, of other congenital malformations.Results: 47.2% of patients had CP and 52.8% had CL±P. 32.2% of all cleft patients had associated congenital malformations. The orofacial region was the most common site, followed by cardiovascular, central nervous, and skeletal systems. Congenital malformations were more common in CP (38.7%), than CL±P(26.4%). Of malformations diagnosed, 63.1% were chromosomal/syndromic anomalies while 36.9% were non-chromosomal/syndromic. Conclusions: Recognition of the spectrum of congenital malformations,associated with orofacial clefting, is essential for further diagnostic testing and in some cases genetic counseling.

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