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


METHODS
Four SNPs within the CRISPLD2 gene domain (rs1546124, rs8061351, rs2326398, rs4783099) were genotyped to test for association via family-based association methods.


METHODS
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).
Letra
Ariadne
A
Menezes
Renato
R
Cooper
Margaret E
ME
Fonseca
Renata F
RF
Tropp
Stephen
S
Govil
Manika
M
Granjeiro
Jose M
JM
Imoehl
Sandra R
SR
Mansilla
M Adela
MA
Murray
Jeffrey C
JC
Castilla
Eduardo E
EE
Orioli
Iêda M
IM
Czeizel
Andrew E
AE
Ma
Lian
L
Chiquet
Brett T
BT
Hecht
Jacqueline T
JT
Vieira
Alexandre R
AR
Marazita
Mary L
ML
D000225:Adenine; D017398:Alternative Splicing / Q000235:genetics; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D015331:Cohort Studies; D003596:Cytosine; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006147:Guanine; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics; D013941:Thymine; D050656:Transcription Factor AP-2 / Q000235:genetics; D044465:White People / Q000235:genetics
C525599:CRISPLD2 protein, human; D015815:Cell Adhesion Molecules; D050835:Interferon Regulatory Factors; D016329:Sp1 Transcription Factor; D050656:Transcription Factor AP-2; D006147:Guanine; D003596:Cytosine; D000225:Adenine; D013941:Thymine
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