Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample

Ishorst, Nina; Francheschelli, Paola; Böhmer, Anne C.; Khan, Mohammad Faisal Jamal; Fricker, Nadine; Little, Julian; Steegers‐Theunissen, R.P.M.; Peterlin, Borut; Nowak, Stefanie; Martini, M.; Kruse, Teresa; Dunsche, Anton; Kreusch, Thomas; Gölz, Lina; Aldhorae, Khalid; Halboub, Esam; Reutter, Heiko; Mossey, Peter; Nöthen, Markus M.; Rubini, Michele; Ludwig, Kerstin U.; Knapp, Michael; Mangold, Elisabeth

doi:10.1002/bdr2.1213

Cited by 12 publications

(6 citation statements)

References 38 publications

(96 reference statements)

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“…In contrast, rare variants may play a substantial role in NSCPO. [ 22 ] In the present study, we identified some new genes that were aberrantly expressed due to aberrant methylation that had not been previously reported in the literature. We validated the methylation levels for DAB1 and FYN , whose expression was significantly downregulated, in a larger sample size by pyrosequencing.…”

Section: Discussionmentioning

confidence: 64%

Genome-Wide Screening of Aberrant Methylation Loci for Nonsyndromic Cleft Lip

Wei

et al. 2018

Chinese Medical Journal

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Background:The pathogenicity of cleft lip (CL) is pretty complicated since it is influenced by the interaction of environment and genetic factors. The purpose of this study was to conduct a genome-wide screening of aberrant methylation loci in partial lesion tissues of patients with nonsyndromic CL (NSCL) and preliminarily validate candidate dysmethylated genes associated with NSCL.Methods:Fifteen healthy and sixteen NSCL fetal lip tissue samples were collected. The Infinium HumanMethylation450 BeadChip was used to screen aberrant methylation loci in three NSCL and three healthy lip tissues. The differential methylation sites and functions of the annotated genes between NSCL and healthy lip tissues were analyzed using minfi package of R software, cluster analysis, Gene Ontology (GO) annotation, and metabolic pathway annotation. Gene expression was assessed in nine differentially methylated genes by real-time polymerase chain reaction (PCR). The transcriptions mRNA levels of three out of nine candidate genes were downregulated remarkably in NSCL lip tissues, and these three genes’ abnormal methylation loci were validated by pyrosequencing in 16 NSCL cases and 15 healthy cases.Results:In total, 4879 sites in the genes of NSCL odinopoeia fetuses showed aberrant methylation when compared with normal lip tissue genome. Among these, 3661 sites were hypermethylated and 1218 sites were hypomethylated as compared to methylation levels in healthy specimens. These aberrant methylation sites involved 2849 genes and were widely distributed among the chromosomes. Most differentially methylated sites were located in cytosine-phosphoric acid-guanine islands. Based on GO analysis, aberrantly methylated genes were involved in 11 cellular components, 13 molecular functions, and a variety of biological processes. Notably, the transcription of DAB1, REELIN, and FYN was significantly downregulated in lesion tissues of NSCL fetus (P < 0.05). Pyrosequencing results validated that there were two loci in DAB1 with high methylation status in patient tissues (P < 0.05).Conclusions:We detected numerous aberrantly methylated loci in lesion tissues of NSCL fetus. Aberrant gene expression in the REELIN signaling pathway might be related with NSCL. Decreased transcription of DAB1, a member of REELIN signal pathway, resulted from its abnormal high methylation, which might be one of the factors underlying the occurrence of NSCL.

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Section: Discussionmentioning

confidence: 64%

Genome-Wide Screening of Aberrant Methylation Loci for Nonsyndromic Cleft Lip

Wei

et al. 2018

Chinese Medical Journal

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“…Based on these genetic findings, non-syndromic CL/P and nonsyndromic CP are considered to have only very limited overlap in terms of their genetic etiology (Cura et al 2016). This is further supported by genome-wide association studies (GWASs) or metaanalyses of GWAS data in different populations that have identified 37 risk loci for non-syndromic CL/P (Birnbaum et al 2009;Mangold et al 2010;Beaty et al 2010Beaty et al , 2013Leslie et al 2015Leslie et al , 2017Yu et al 2017;Ludwig et al 2017a;Ludwig et al 2017b;Ishorst et al 2018), but just one replicated finding for nonsyndromic CP Mangold et al 2016).…”

Section: Introductionmentioning

confidence: 93%

Association between a common missense variant in LOXL3 gene and the risk of non‐syndromic cleft palate

Khan

Little

Mossey

et al. 2018

Congenital Anomalies

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To investigate possible association between functional common variants in the lysyl oxidase like 3 gene and non-syndromic cleft palate we selected a common missense variant p.Ile615Phe (rs17010021), which was predicted to have a probably damaging effect on the lysyl oxidase like 3 enzyme. We genotyped 258 non-syndromic cleft palate case-parent triads of European origin and tested genetic association using the transmission disequilibrium test and log-linear regression analyses of genotypic relative risks and of parent-of-origin effects. The observed genotype frequency in parents was in Hardy-Weinberg equilibrium. Compared with wild-type Ile/Ile homozygotes, the relative risks for Phe/Phe homozygote infants was 6.87 (P value 3.0 × 10 ), while that for Ile/Phe heterozygotes was not significant. Assuming an autosomal recessive model, the relative risks for Phe/Phe genotype resulted 10.54 (P value 2.9 × 10 ), with a 3.6% population attributable risk. No parent-of-origin effect was observed. The identification in lysyl oxidase like 3 of a missense variant which under a recessive model associates with 10-fold increased risk of non-syndromic cleft palate supports the hypothesis that the genetic etiology of this congenital anomaly includes relatively uncommon recessive variants with moderate penetrance and located in genes which are also involved in syndromes that include cleft palate as part of the phenotype. Our findings require functional validation and replication in a larger independent genetic association study.

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“…700 live births worldwide each year, and have been divided historically into cleft lip, with or without cleft palate (CL/P), and cleft palate only (CP), due to the distinct developmental origins of the lip and the palate (Figure 5). While their reported prevalences vary considerably according to ancestral origin, Asians are the most frequently affected population, with birth prevalence rates as high as 1 in 500 live births, followed by Caucasians with a prevalence rate of about 1 in 1000 live births, and African populations showing the lowest prevalence rates at approximately 1 in 2500 live births (Kadir et al, 2017;Mossey et al, 2017;Ishorst et al, 2018). The presence of CL/P also differs by sex and laterality, with CL/P being more common in males than females at a 2:1 ratio, and CP being more common in females, meanwhile unilateral left CL/P is more common than unilateral right CL/P at a 2:1 ratio.…”

Section: Cleft Lip And/or Palatementioning

confidence: 99%

Extracellular Matrix Composition and Remodeling: Current Perspectives on Secondary Palate Formation, Cleft Lip/Palate, and Palatal Reconstruction

Paiva

Maas

Santos

et al. 2019

Front. Cell Dev. Biol.

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Craniofacial development comprises a complex process in humans in which failures or disturbances frequently lead to congenital anomalies. Cleft lip with/without palate (CL/P) is a common congenital anomaly that occurs due to variations in craniofacial development genes, and may occur as part of a syndrome, or more commonly in isolated forms (non-syndromic). The etiology of CL/P is multifactorial with genes, environmental factors, and their potential interactions contributing to the condition. Rehabilitation of CL/P patients requires a multidisciplinary team to perform the multiple surgical, dental, and psychological interventions required throughout the patient's life. Despite progress, lip/palatal reconstruction is still a major treatment challenge. Genetic mutations and polymorphisms in several genes, including extracellular matrix (ECM) genes, soluble factors, and enzymes responsible for ECM remodeling (e.g., metalloproteinases), have been suggested to play a role in the etiology of CL/P; hence, these may be considered likely targets for the development of new preventive and/or therapeutic strategies. In this context, investigations are being conducted on new therapeutic approaches based on tissue bioengineering, associating stem cells with biomaterials, signaling molecules, and innovative technologies. In this review, we discuss the role of genes involved in ECM composition and remodeling during secondary palate formation and pathogenesis and genetic etiology of CL/P. We also discuss potential therapeutic approaches using bioactive molecules and principles of tissue bioengineering for state-of-the-art CL/P repair and palatal reconstruction.

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Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample

Cited by 12 publications

References 38 publications

Genome-Wide Screening of Aberrant Methylation Loci for Nonsyndromic Cleft Lip

Genome-Wide Screening of Aberrant Methylation Loci for Nonsyndromic Cleft Lip

Association between a common missense variant in LOXL3 gene and the risk of non‐syndromic cleft palate

Extracellular Matrix Composition and Remodeling: Current Perspectives on Secondary Palate Formation, Cleft Lip/Palate, and Palatal Reconstruction

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