CRISPLD2 variants including a C471T silent mutation may contribute to nonsyndromic cleft lip with or without cleft palate

Ariadne Letra, Renato Menezes, Margaret E. Cooper, Renata F. Fonseca, Stephen Tropp, Manika Govil, Jose M. Granjeiro, Sandra R. Imoehl, M. Adela Mansilla, Jeffrey C. Murray, Eduardo E. Castilla, Iêda M. Orioli, Andrew E. Czeizel, Lian Ma, Brett T. Chiquet, Jacqueline T. Hecht, Alexandre R. Vieira, Mary L. Marazita

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Objective: To assess the association between nonsyndromic (NS) cleft lip with or without cleft palate (CL(P)) and single-nucleotide polymorphisms (SNPs) within the CRISPLD2 gene (cysteine-rich secretory protein LCCL domain containing 2). Design: Four SNPs within the CRISPLD2 gene domain (rs1546124, rs8061351, rs2326398, rs4783099) were genotyped to test for association via family-based association methods. Participants: A total of 5826 individuals from 1331 families in which one or more family member is affected with CL(P). Results: Evidence of association was seen for SNP rs1546124 in U.S. (p = .02) and Brazilian (p = .04) Caucasian cohorts. We also found association of SNP rs1546124 with cleft palate alone (CP) in South Americans (Guatemala and ECLAMC) and combined Hispanics (Guatemala, ECLAMC, and Texas Hispanics; p = .03 for both comparisons) and with both cleft lip with cleft palate (CLP; p = .04) and CL(P) (p = .02) in North Americans. Strong evidence of association was found for SNP rs2326398 with CP in Asian populations (p = .003) and with CL(P) in Hispanics (p = .03) and also with bilateral CL(P) in Brazilians (p = .004). In Brazilians, SNP rs8061351 showed association with cleft subgroups incomplete CL(P) (p = .004) and unilateral incomplete CL(P) (p = .003). Prediction of SNP functionality revealed that the C allele in the C471T silent mutation (overrepresented in cases with CL(P) presents two putative exonic splicing enhancer motifs and creates a binding site AP-2 alpha, a transcription factor involved in craniofacial development. Conclusions: Our results support the hypothesis that variants in the CRISPLD2 gene may be involved in the etiology of NS CL(P).

Original languageEnglish
Pages (from-to)363-370
Number of pages8
JournalCleft Palate-Craniofacial Journal
Issue number4
Publication statusPublished - Jul 1 2011



  • CRISPLD2 gene
  • Cleft lip
  • Cleft palate
  • Subphenotypes

ASJC Scopus subject areas

  • Oral Surgery
  • Otorhinolaryngology

Cite this

Letra, A., Menezes, R., Cooper, M. E., Fonseca, R. F., Tropp, S., Govil, M., Granjeiro, J. M., Imoehl, S. R., Mansilla, M. A., Murray, J. C., Castilla, E. E., Orioli, I. M., Czeizel, A. E., Ma, L., Chiquet, B. T., Hecht, J. T., Vieira, A. R., & Marazita, M. L. (2011). CRISPLD2 variants including a C471T silent mutation may contribute to nonsyndromic cleft lip with or without cleft palate. Cleft Palate-Craniofacial Journal, 48(4), 363-370.