Non-syndromic Cleft Lip and Palate Polymorphisms Affect Normal Lip Morphology

Caryl Wilson-Nagrani,Stephen Richmond,Lavinia Paternoster

doi:10.3389/fgene.2018.00413

Abstract

Non-syndromic cleft lip with or without palate (NSCL/P) is a frequent malformation of the facial region. Genetic variants (SNPs) within nineteen loci have been previously associated with NSCL/P in GWAS studies of European individuals. These common variant SNPs may have subtler effects on the morphology of the lip and face in unaffected individuals. Several studies have investigated the genetic influences on facial morphology using land-marking methods, but these landmarks are sparse in the lip region. The aim of this study is to assess for associations between the nineteen NSCL/P SNPs and normal lip phenotypes, using a detailed categorical scale. Three-dimensional laser scanned facial images were obtained of 4,747 subjects recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) and genetic data was available for 3,643 of them. A polygenetic risk score (PRS) combining the nineteen NSCL/P SNPs was associated with V-shaped Cupid's bow (P = 3 × 10−4) and narrow philtrum (P = 2 × 10−4) phenotypes. Analysis of individual SNPs found strong evidence for association between rs227731 and skeletal II pattern (P = 5 × 10−6). This study finds that known NSCL/P SNPs affect lip phenotypes in the general population, and an increased PRS is associated with narrow philtrum and V-shaped Cupid's bow. However, the difference in NSCL/P PRS between people with and without certain lip features is unlikely to be great enough to serve as a useful marker of NSCL/P risk.

Highlights

Cleft lip with or without palate (CL/P) is the most common craniofacial disorder worldwide
There was little evidence for an association between the Non-syndromic cleft lip with or without palate (NSCL/P) polygenetic risk score (PRS) and skeletal pattern (P = 0.18), indicating that the genetic overlap between these two phenotypes might be limited to this one locus, rather than skeletal pattern II being a general marker of high NSCL/P risk
We have identified some interesting shared genetic effects between NSCL/P and normal lip morphology, TABLE 4 | Selection of NSCL/P SNPs nominally associated (P < 0.01) with lip phenotypes

Summary

Introduction

Cleft lip with or without palate (CL/P) is the most common craniofacial disorder worldwide. It has varying prevalence ranging from approximately 1 in 500 to 1 in 1,000 live births depending on ethnicity and country (Mossey et al, 2009; Klotz et al, 2010). Cleft palate only (CPO) is considered as a separate entity to cleft lip and/or palate, and is thought to have a distinct etiology (Mossey et al, 2009). The corrective treatment of CL/P requires extensive multi-disciplinary management, and poses an enormous burden on upon those affected, and their families and social and health care systems (Mossey et al, 2009). There is significant interest in identifying non-clefting phenotypic markers that might be used for risk prediction in the general population, which would benefit the development of prevention strategies.

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