AIM: Non syndromic cleft lip and/or palate (NSCL/P) is considered a genetically complex trait supporting a multifactorial model of inheritance, in which genetic risk factor of small individual impact may interact with environmental contributions. The aim of the present work is to review the current literature regarding genetics of NSCL/P, focusing on the multiple methods of genetic investigation. Furthermore, genes and genetic loci best-supported as involved in NSCL/P are discussed. METHODS: A Medline and Scopus search was conducted in order to identify publications related to the topic, with no limitations of language or time period. Entry words included: "orofacial cleft", "cleft lip", "cleft palate", genetics", "nonsyndromic". Relevant information was also derived from reference lists of the publications retrived. RESULTS: Genetic approaches to non-syndromic CLP have included: linkage analysis, association studies, identification of chromosomal anomalies or microdeletions in cases and direct sequencing of affected individuals. These methods can be applied to candidate genes or genome-wide strategies can be used. To date, there have been eight independent genomic wide association studies (GWASs) for CL/P, a genome-wide meta-analyses of two CL/P GWASs, and two GWASs for isolated left palate (CP). For CL/P at least 20 different loci have been confirmed with statistical and biological supporting data. The genes and genetic loci best supported as involved in NSCL/P are: interferon regulatory factor 6 (IRF6) on chromosome 1q32.2, MAFB on 20q12, ARHGAP29 on 1p22, gene desert r egion on 8q24, ventral anterior homeobox 1 (VAX1) on 10q25.3, paired box protein Pax-7 (PAX7) on 1p36.13, forkhead box E1 (FOXE1) on 9q22.33, transforming growth factor alpha (TGFA) on 2p13.3, tumor protein p63 (TP63) on 3q28, bone morphogenetic protein 4 (BMP4) on 14q22.2. Notably, mutations in IRF6 were first discovered to be etiologic in autosomal-dominant clefting syndrome (Van der Woude syndrome); subsequently, the causative role of this gene has been identified also for NSCL/P and independently replicated across the studies. CONCLUSIONS: Among the new genomic tools, GWASs are considered ideal for dissecting common, complex (non-single-gene) traits and NSCL/P is one of the few birth-onset disorders to have been investigated with this powerful method. Collectively, these studies have demonstrated that orofacial clefts exhibit significant genetic heterogeneity, having successfully identified multiple genome-wide significant associations with CL/P as well as potential gene-environment interactions for CP. However, with the important exception of IRF6, the significant risk loci from GWAS of NSCL/P are diverse than the significant risk loci from genome-wide linkage analyses, this highlighting the different strengths of the two approaches.
GENETICS OF NON-SYNDROMIC CLEFT LIP AND PALATE: A CRITICAL REVIEW
CASSI, DIANA;PIANCINO, MARIA GRAZIA
2017-01-01
Abstract
AIM: Non syndromic cleft lip and/or palate (NSCL/P) is considered a genetically complex trait supporting a multifactorial model of inheritance, in which genetic risk factor of small individual impact may interact with environmental contributions. The aim of the present work is to review the current literature regarding genetics of NSCL/P, focusing on the multiple methods of genetic investigation. Furthermore, genes and genetic loci best-supported as involved in NSCL/P are discussed. METHODS: A Medline and Scopus search was conducted in order to identify publications related to the topic, with no limitations of language or time period. Entry words included: "orofacial cleft", "cleft lip", "cleft palate", genetics", "nonsyndromic". Relevant information was also derived from reference lists of the publications retrived. RESULTS: Genetic approaches to non-syndromic CLP have included: linkage analysis, association studies, identification of chromosomal anomalies or microdeletions in cases and direct sequencing of affected individuals. These methods can be applied to candidate genes or genome-wide strategies can be used. To date, there have been eight independent genomic wide association studies (GWASs) for CL/P, a genome-wide meta-analyses of two CL/P GWASs, and two GWASs for isolated left palate (CP). For CL/P at least 20 different loci have been confirmed with statistical and biological supporting data. The genes and genetic loci best supported as involved in NSCL/P are: interferon regulatory factor 6 (IRF6) on chromosome 1q32.2, MAFB on 20q12, ARHGAP29 on 1p22, gene desert r egion on 8q24, ventral anterior homeobox 1 (VAX1) on 10q25.3, paired box protein Pax-7 (PAX7) on 1p36.13, forkhead box E1 (FOXE1) on 9q22.33, transforming growth factor alpha (TGFA) on 2p13.3, tumor protein p63 (TP63) on 3q28, bone morphogenetic protein 4 (BMP4) on 14q22.2. Notably, mutations in IRF6 were first discovered to be etiologic in autosomal-dominant clefting syndrome (Van der Woude syndrome); subsequently, the causative role of this gene has been identified also for NSCL/P and independently replicated across the studies. CONCLUSIONS: Among the new genomic tools, GWASs are considered ideal for dissecting common, complex (non-single-gene) traits and NSCL/P is one of the few birth-onset disorders to have been investigated with this powerful method. Collectively, these studies have demonstrated that orofacial clefts exhibit significant genetic heterogeneity, having successfully identified multiple genome-wide significant associations with CL/P as well as potential gene-environment interactions for CP. However, with the important exception of IRF6, the significant risk loci from GWAS of NSCL/P are diverse than the significant risk loci from genome-wide linkage analyses, this highlighting the different strengths of the two approaches.
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