scholarly journals Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate

2019 ◽  
Author(s):  
Nicholas J. Marini ◽  
Kripa Asrani ◽  
Wei Yang ◽  
Jasper Rine ◽  
Gary M Shaw
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Rare Variants ◽  
Fold Increase ◽  
Loss Of Function ◽  
Craniofacial Malformation ◽  
Gene Level ◽  
Multiple Case ◽  
Genetic And Environmental Factors ◽  
Coding Variants

ABSTRACTCleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 non-malformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = 0.03), including multiple case occurrences of a rare frameshift mutation (K400fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.

SUMO1 as a candidate gene for non-syndromic cleft lip with or without cleft palate: No evidence for the involvement of common or rare variants in Central European patients

2011 ◽  
Vol 75 (1) ◽  
pp. 49-52 ◽  
Author(s):  
Nilma Almeida de Assis ◽  
Stefanie Nowak ◽  
Kerstin U. Ludwig ◽  
Heiko Reutter ◽  
Jennifer Vollmer ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Candidate Gene ◽  
Cleft Lip ◽  
Rare Variants ◽  
Central European

scholarly journals Cárie Dentária em Indivíduos com Fissuras Labiopalatinas: Revisão de Literatura

UNICIÊNCIAS ◽  
2021 ◽  
Vol 24 (1) ◽  
pp. 112-117
Author(s):  
Andreza Maria Fábio Aranha ◽  
Amanda Alves de Oliveira ◽  
Alexandre Meireles Borba ◽  
Luiz Evaristo Ricci Volpato
Keyword(s):  
Oral Health ◽  
Dental Caries ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Public Health Practice ◽  
Well Being ◽  
Individualized Approach ◽  
Genetic And Environmental Factors ◽  
Isolated Cleft Palate

As fissuras labiopalatinas (FLP) são as malformações congênitas mais comuns da região craniofacial e apresentam diferentes fenótipos e características clínicas, que diferem entre si de acordo com as estruturas anatômicas envolvidas: fissura de lábio, fissura de lábio e palato e fissura de palato isolada. A etiologia das FLP é multifatorial e inclui fatores genéticos e ambientais. O objetivo do presente estudo foi investigar o papel das fissuras labiopalatinas na prevalência de cárie dentária por meio de uma revisão na literatura. O defeito anatômico que envolve o rebordo alveolar e/ou o palato pode resultar em agenesias dentárias, dentes supranumerários, anomalias de forma e estrutura, bem como atresia maxilar, mordidas cruzadas posteriores e apinhamentos dentários. Também, a presença da FLP pode resultar aos indivíduos problemas durante alimentação, pronúncia de alguns fonemas, audição e integração social, o que poderia afetar a qualidade de vida do indivíduo e da dinâmica familiar. Quando a saúde bucal de crianças e adolescentes com FLP foi investigada, maior retenção do biofilme microbiano nas superfícies dentárias, de inflamação gengival e maior ocorrência de cárie dentária foram observados. Para um diagnóstico e tratamento adequados, é fundamental uma abordagem multidisciplinar, individualizada, para orientação e planejamento do tratamento dos indivíduos com a malformação, desde o nascimento até a fase adulta. O conhecimento dos efeitos da FLP na saúde bucal e no bem-estar dos indivíduos e das famílias afetadas é fundamental para mudanças nas políticas públicas das práticas de saúde e redução da sobrecarga da presença da malformação congênita.   Palavras-chave: Cárie Dentária. Fenda Labial. Fissura Palatina. Saúde Bucal   Abstract Cleft lip and palate (CLP) are the most common congenital malformations of the craniofacial region and they present different phenotypes and clinical characteristics, which differ according to the anatomical structures involved: cleft lip, cleft lip and palate and isolated cleft palate. The etiology of CLP is multifactorial and includes genetic and environmental factors. The aim of this study was to investigate the role of cleft lip and palate in the prevalence of dental caries through a literature review. The anatomical defect involving the alveolar ridge and / or the palate can result in dental agenesis, supernumerary teeth, anomalies in shape and structure, as well as maxillary atresia, posterior cross bites and dental crowding. Also, the presence of CLP can result in problems for individuals during feeding, pronunciation of some phonemes, hearing and social integration, which could affect the individual's quality of life and family dynamics. When the oral health of children and adolescents with CLP was investigated, greater retention of microbial biofilm on dental surfaces, gingival inflammation and the occurrence of dental caries were observed. For an adequate diagnosis and treatment, a multidisciplinary and individualized approach is essential to guide and plan the treatment of individuals with the malformation, from birth to adulthood. The knowledge of the effects of FLP on oral health and on the well-being of affected individuals and families is fundamental to changes in public health practice policies and to reduce the burden of the presence of the congenital malformation.   Keywords:  Cleft Lip. Cleft Palate. Dental Caries. Oral Health.

scholarly journals Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate

2018 ◽  
Vol 55 (5) ◽  
pp. 736-742 ◽  
Author(s):  
Lord Jephthah Joojo Gowans ◽  
Ganiyu Oseni ◽  
Peter A. Mossey ◽  
Wasiu Lanre Adeyemo ◽  
Mekonen A. Eshete ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Soft Palate ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Sequence Data ◽  
Regulatory Elements ◽  
The Face ◽  
Sub Saharan ◽  
African Patients ◽  
Coding Variants

Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate. Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature. Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene. Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.

Epidemiology of cleft lip with or without cleft palate in Thais

2017 ◽  
Vol 10 (4) ◽  
pp. 335-338 ◽  
Author(s):  
Rungnapa Ittiwut ◽  
Pichit Siriwan ◽  
Kanya Suphapeetiporn ◽  
Vorasuk Shotelersuk
Keyword(s):  
Family History ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Epidemiological Studies ◽  
Retrospective Case ◽  
Oral Clefts ◽  
Oral Cleft ◽  
History Of ◽  
Maternal Consumption ◽  
Genetic And Environmental Factors

Abstract Background Oral clefts, including cleft lip (CL), CL with cleft palate (CL/CP), and cleft palate only (CPO), are among the most common birth defects, and if left untreated can cause significant morbidity. Causes are complex and involve both genetic and environmental factors. Several studies have demonstrated the highest prevalence of oral clefts being in Asian, white, and African populations. However, there have been very few epidemiological studies of oral clefts in Thais. Objectives To describe the epidemiology and factors associated with oral clefts in Thais. Methods This retrospective case-control observational study included individuals from numerous regions in Thailand. We reviewed data regarding 784 patients with an oral cleft collected in questionnaires as part of the Thai nationwide Smart Smile and Speech Project from 2006 to 2014. Data regarding patients with oral clefts were analyzed, and compared with data regarding 187 unaffected controls. Results Of 784 cases, CL/CP accounted for 59.8%, CPO 21.9%, and CL 18.3%. A family history of oral clefts was detected in all 3 types (P < 0.001). Maternal use of any drugs or herbal medicine not prescribed by physicians during pregnancy in cases of CPO (P = 0.049) and maternal consumption of alcohol during pregnancy in cases of CL/CP (P = 0.047) were significantly higher than that by mothers of controls. Conclusions CL/CP is the most common type of oral cleft. A family history of oral clefts, and maternal consumption of alcohol or nonprescribed drugs are positively associated with oral clefts in Thais.

scholarly journals Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate

2017 ◽  
Vol 97 (1) ◽  
pp. 41-48 ◽  
Author(s):  
M.A. Eshete ◽  
H. Liu ◽  
M. Li ◽  
W.L. Adeyemo ◽  
L.J.J Gowans ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
De Novo ◽  
Phosphorylation Site ◽  
Dominant Negative ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Sumoylation Site ◽  
Genetic Etiology

In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.

Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate

2015 ◽  
Vol 36 (11) ◽  
pp. 1029-1033 ◽  
Author(s):  
Luciano Abreu Brito ◽  
Guilherme Lopes Yamamoto ◽  
Soraia Melo ◽  
Carolina Malcher ◽  
Simone Gomes Ferreira ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Rare Variants ◽  
Genetic Etiology ◽  
Epithelial Cadherin

scholarly journals Rare Coding Variants Associated with Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-ancestry Analysis

2021 ◽  
Author(s):  
Seung Hoan Choi ◽  
Sean J. Jurgens ◽  
Christopher M. Haggerty ◽  
Amelia W. Hall ◽  
Jennifer L. Halford ◽  
...  
Keyword(s):  
Large Scale ◽  
Rare Variants ◽  
Sequence Data ◽  
Susceptibility Genes ◽  
P Wave ◽  
Cardiac Conduction ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Electrocardiographic Intervals ◽  
Coding Variants

Background - Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between ECG intervals and rare genetic variation at a population level are poorly understood. Methods - Using a discovery sample of 29,000 individuals with whole-genome sequencing from TOPMed and replication in nearly 100,000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured ECG traits (RR, P-wave, PR, and QRS intervals and corrected QT interval [QTc]). Results - We found that rare variants associated with population-based ECG intervals identify established monogenic SCD genes ( KCNQ1 , KCNH2 , SCN5A ), a controversial monogenic SCD gene ( KCNE1 ), and novel genes ( PAM , MFGE8 ) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of first-degree atrioventricular block ( P =8.4x10 -5 ). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked QTc prolongation ( P =4x10 -25 ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal ECG intervals. Conclusions - Our findings indicate that large-scale high-depth sequence data and ECG analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked ECG interval prolongation.

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