Open Access Open Badges Research article

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

Samuel G Younkin1*, Robert B Scharpf2, Holger Schwender3, Margaret M Parker4, Alan F Scott5, Mary L Marazita6, Terri H Beaty4 and Ingo Ruczinski1

Author Affiliations

1 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA

2 Department of Oncology, Johns Hopkins School of Medicine, Baltimore MD, USA

3 Mathematical Institute, Heinrich Heine University, Düsseldorf, Germany

4 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA

5 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD, USA

6 School of Dental Medicine, University of Pittsburgh, Pittsburgh PA, USA

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BMC Genetics 2014, 15:24  doi:10.1186/1471-2156-15-24

Published: 14 February 2014



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. 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.


We 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.


This 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.

Oral clefts; DNA copy numbers; de novo deletions; Case-parent trios