Orofacial development is a multifaceted process involving tightly regulated genetic signaling networks, that when perturbed, lead to orofacial abnormalities including cleft lip and/or cleft palate. We and others have shown an association between the cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) gene and nonsyndromic cleft lip with or without cleft palate (NSCLP). Further, we demonstrated that knockdown of Crispld2 in zebrafish alters neural crest cell migration patterns resulting in abnormal jaw and palate development.

In this study, researchers from the University of Texas Health Science Center at Houston performed RNA profiling in zebrafish embryos and identified 249 differentially expressed genes following knockdown of Crispld2. In silico pathway analysis identified a network of seven genes previously implicated in orofacial development for which differential expression was validated in three of the seven genes. Single nucleotide variant (SNV) genotyping of these three genes revealed significant associations between NSCLP and FOS in the nonHispanic white (NHW) families and MMP2 in the Hispanic families. Nominal association was found between NSCLP and CASP8. Overtransmission of MMP2 haplotypes were identified in the Hispanic families . Significant gene-gene interactions were identified for FOS-MMP2 in the NHW families and for CASP8-FOS in the NHW simplex family subgroup. Additional in silico analysis revealed a novel gene regulatory network including five of these newly identified and 23 previously reported NSCLP genes. These results demonstrate that animal models of orofacial clefting can be powerful tools to identify novel candidate genes and gene regulatory networks underlying NSCLP.

Paradigm used to identify novel NSCLP genes

LC Sciences

Chiquet BT, Yuan Q, Swindell EC, Maili L, Plant R, Dyke J, Boyer R, Teichgraeber JF, Greives MR, Mulliken JB, Letra A, Blanton SH, Hecht JT. (2018) Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes. Eur J Hum Genet [Epub ahead of print]. [abstract]

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