A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk

Samuel G Younkin,Holger Schwender,Mary L Marazita,Robert B Scharpf,Alan F Scott,Terri H Beaty,Ingo Ruczinski,Margaret M Parker

doi:10.1186/1471-2156-15-24

Abstract

BackgroundCopy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects (including clefts) have been shown to carry small and large chromosomal deletions. In this paper we investigate de novo deletions defined as DNA segments missing in an oral cleft proband but present in both unaffected parents. We compare de novo deletion frequencies in children of European ancestry with an isolated, non-syndromic oral cleft to frequencies in children of European ancestry from randomly sampled trios.ResultsWe identified a genome-wide significant 62 kilo base (kb) non-coding region on chromosome 7p14.1 where de novo deletions occur more frequently among oral cleft cases than controls. We also observed wider de novo deletions among cleft lip and palate (CLP) cases than seen among cleft palate (CP) and cleft lip (CL) cases.ConclusionsThis study presents a region where de novo deletions appear to be involved in the etiology of oral clefts, although the underlying biological mechanisms are still unknown. Larger de novo deletions are more likely to interfere with normal craniofacial development and may result in more severe clefts. Study protocol and sample DNA source can severely affect estimates of de novo deletion frequencies. Follow-up studies are needed to further validate these findings and to potentially identify additional structural variants underlying oral clefts.

Highlights

Copy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects have been shown to carry small and large chromosomal deletions
These authors confirmed several de novo deletions in some of these candidate genes, in particular SUMO1, TBX1, and TFAP2A, raising the possibility that genes or regulatory elements contained within deleted regions might play a role in the etiology of oral clefts
MD: de novo deletions with coverage of at least ten markers inferred by MinimumDistance [44]; PennCNV: de novo deletions with coverage of at least ten markers inferred by PennCNV [43]

Summary

Introduction

Copy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects (including clefts) have been shown to carry small and large chromosomal deletions. Shi et al used SNP genotyping, DNA sequencing, highresolution DNA microarray analysis, and long-range PCR to characterize chromosomal deletions in 333 candidate genes for orofacial clefting in 2,823 samples from 725 two and three generation families ascertained through a proband with a CL/P [27]. These authors confirmed several de novo deletions (defined as DNA segments missing in an oral cleft proband but present in both parents in two copies) in some of these candidate genes, in particular SUMO1, TBX1, and TFAP2A, raising the possibility that genes or regulatory elements contained within deleted regions might play a role in the etiology of oral clefts. High rates of Mendelian inconsistencies were observed in 11 different genes, suggesting the existence of additional micro-deletions among oral cleft cases

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