Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

Abstract

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10−8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

Genetics and signaling mechanisms of orofacial clefts

“…Components of the Sonic hedgehog (SHH) and wingless‐type MMTV integration site family (WNT) pathways were also identified, including PTCH1 and WNT9B , and the latter is a homolog of an important CL/P mouse model gene (Juriloff, Harris, McMahon, Carroll, & Lidral, 2006; Y. Yu et al, 2017). Many genes previously linked with OFCs were also identified/confirmed in the Yu et al study, as well as another recently performed extensive GWAS (L. Huang et al, 2019).…”

“…OFCs are typically classified as either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO). As the processes that govern lip and palate formation differ along with their respective causes and risk factors, it is becoming more common for studies to group CL/P patients with cleft lip only (CLO) separately from those with cleft lip and palate (CLP) to more accurately investigate the causal relationships between potential influences and specific types of resulting OFCs (L. Huang et al, 2019). This review is a part of a series discussing the underlying mechanisms that contribute to OFC formation.…”

Factores asociados a la presencia de fisura labiopalatina en recién nacidos en un hospital peruano de tercer nivel de atención. Un estudio de casos y controles

“…Las malformaciones congénitas son defectos estructurales del desarrollo embrionario que afectan aproximadamente entre el 3 y el 5 % de los nacidos vivos, pudiendo detectarse en forma prenatal, al nacer o posteriormente. La fisura del labio y paladar son causados por la disrupción de la estructura facial normal y en su mayoría ocurren como defectos únicos; son clasificados como defectos no sindrómicos e incluyen: fisura labial, fisura del paladar y fisura labiopalatina [1] .…”

“…Su etiología no se encuentra totalmente aclarada, pero se ha considerado que tanto factores genéticos como ambientales contribuyen a un origen multifactorial de las fisuras orales no sindrómicas, representando una condición genética en cerca del 25 % de los casos [4,[11][12][13][14] . Los estudios de asociación genómica (GWAS, por sus siglas en inglés) han detectado hasta 46 genes o loci asociados, siendo el gen IRF6 uno de los que presentarían mayor asociación en diferentes poblaciones [1] .…”

An Association Study of Candidate Gene Variants in Chinese Nonsyndromic Cleft Lip with or without Palate Subjects

“…The prevalence of NSCL/P in China was 1.22/1000 [3].It is considered to be a multifactorial disease with both genetic and environmental factors contributing to the etiology. Nonsyndromic cleft palate only (NSCPO) is to some extent different though not completely distinct from NSCL/P in genetic mechanism [4].…”