Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts

Abstract

Orofacial clefts (OFCs) represent a large fraction of human birth defects and are one of the most common phenotypes affected by large copy number variants (CNVs). Due to the limited number of CNV patients in individual centers, CNV analyses of a large number of OFC patients are challenging. The present study analyzed 249 genomic deletions and 226 duplications from a cohort of 312 OFC patients reported in two publicly accessible databases of chromosome imbalance and phenotype in humans, DECIPHER and ECARUCA. Genomic regions deleted or duplicated in multiple patients were identified, and genes in these overlapping CNVs were prioritized based on the number of genes encompassed by the region and gene expression in embryonic mouse palate. Our analyses of these overlapping CNVs identified two genes known to be causative for human OFCs, SATB2 and MEIS2, and 12 genes (DGCR6, FGF2, FRZB, LETM1, MAPK3, SPRY1, THBS1, TSHZ1, TTC28, TULP4, WHSC1, WHSC2) that are associated with OFC or orofacial development. Additionally, we report 34 deleted and 24 duplicated genes that have not previously been associated with OFCs but are associated with the BMP, MAPK and RAC1 pathways. Statistical analyses show that the high number of overlapping CNVs is not due to random occurrence. The identified genes are not located in highly variable genomic regions in healthy populations and are significantly enriched for genes that are involved in orofacial development. In summary, we report a CNV analysis pipeline of a large cohort of OFC patients and identify novel candidate OFC genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1606-x) contains supplementary material, which is available to authorized users.

Application of high‐resolution array platform for genome‐wide copy number variation analysis in patients with nonsyndromic cleft lip and palate

“…More recently, a systematic analysis of CNVs of a large cohort of orofacial cleft patients identified known causative genes for CLP SATB2 and MEIS2 and 12 other genes ( DGCR6, FGF2, FRZB, LETM1, MAPK3, SPRY1, THBS1, TSHZ1, TTC28, TULP4, WHSC1, WHSC2 ) . This study also reported 34 deleted and 24 duplicated genes associated with novel candidates genes involved in signaling pathways in orofacial development . Additionally, according to this study, although the genes SATB2 and MEIS2 have been classified as CLP causative genes, they appear to be frequently affected by small deletions in healthy individuals.…”

“…18 This study also reported 34 deleted and 24 duplicated genes associated with novel candidates genes involved in signaling pathways in orofacial development. 20 Additionally, according to this study, although the genes SATB2 and MEIS2 have been classified as CLP causative genes, they appear to be frequently affected by small deletions in healthy individuals. Therefore, the notion that CNVs are also abundantly present in healthy populations challenges the interpretation of the clinical significance of detected CNVs in patients with cleft and/or lip palate.…”

SATB2‐associated syndrome: Mechanisms, phenotype, and practical recommendations

“…Only papers in which the alteration of SATB2 was well documented with supplemental molecular techniques (e.g., microarrays, fine mapping, FISH, PCR) were included. Similarly, several other cases of deletions that encompass SATB2 have been briefly mentioned in large studies although with no full phenotypic description and therefore, were excluded from this review [Talkowski et al, ; Conte et al, ]. The included cases are shown in Figure , while the phenotypic features are presented in Table .…”

Unmasking familial CPX by WES and identification of novel clinical signs

“…Missense variants were considered as possibly pathogenic only if predicted to be possibly/probably damaging in at least three out of seven, seven variant in silico classifiers (Sift, Polyphen, LRT, Mutation taster, Mutation assessor, FATHMM, DEOGEN). We considered a list of 89 genes implicated in both syndromic and non‐syndromic CLP (Stanier & Moore, ), nsCLP candidate genes (Leslie & Murray, ) and a selection of CLP candidate genes that we gathered from publications (Conte et al, ; Jugessur, Farlie, & Kilpatrick, ; Kousa, Mansour, Seada, Matoo, & Schutte, ; Lough, Byrd, Spitzer, & Williams, ) including recently confirmed CLP genes such as ARHGAP29 (Leslie et al, ) and GRHL3 (Peyrard‐Janvid et al, ). Gene list is available upon request.…”