Abstract
rs7590268 present on the 2p21 locus was identified to be associated with non-syndromic cleft lip with or without cleft palate (NSCL/P) in several populations, including the Chinese Han population, indicating that 2p21 was a susceptibility locus for NSCL/P. However, previous studies have only identified common single-nucleotide polymorphism (SNP) within the THADA gene, neglecting the rare variants and other genes in 2p21; thus, this study was designed to investigate additional variants and novel susceptibility genes in 2p21. A total of 159 NSCL/P patients and 542 controls were recruited in the discovery phase, whereas 1830 NSCL/P patients and 2,436 controls were recruited in the replication phase. After targeted region sequencing, we performed association and burden analyses for the common and rare variants, respectively. Furthermore, RNA-seq, proliferation assay and cell cycle analysis were performed to clarify the possible function of the candidate gene ZFP36L2. Association analysis showed that four SNPs were specifically associated with non-syndromic cleft lip only (NSCLO) and two SNPs were associated with both NSCLO and NSCL/P. Burden analysis indicated that ZFP36L2 was associated with NSCLO (p = .0489, OR = 2.41, 95% CI: 0.98–5.90). Moreover, SNPs in the ZFP36L2 targeted gene JUP were also associated with NSCLO. ZFP36L2 also inhibited cell proliferation and induced G2 phase arrest in the GMSM-K cell line. Therefore, we proposed that ZFP36L2 is a novel susceptibility gene of NSCLO in the 2p21 locus, which could lead to NSCLO by modulating cell proliferation and cycle.
Highlights
Non-syndromic orofacial clefts (NSOFCs), which usually occur without any other physiological abnormalities, are one of the most common birth defects
NSOFCs are commonly divided into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and non-syndromic cleft palate only (NSCPO), which have been historically regarded as etiologically distinct phenotypes, because they differ in epidemiology and family patterns, as well as in the developmental origin of the lip and palate (Marazita, 2012)
From the 159 NSCL/P cases, we identified a total of 2,352 Single-nucleotide variants (SNVs) and 552 insertion/deletions, including variants located in exons, splice sites, introns, untranslated region (UTR), and intergenic regions (Supplementary Figure S3)
Summary
Non-syndromic orofacial clefts (NSOFCs), which usually occur without any other physiological abnormalities, are one of the most common birth defects. NSOFCs are commonly divided into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and non-syndromic cleft palate only (NSCPO), which have been historically regarded as etiologically distinct phenotypes, because they differ in epidemiology and family patterns, as well as in the developmental origin of the lip and palate (Marazita, 2012). NSCL/P, on the other hand, includes two phenotypes: non-syndromic cleft lip only (NSCLO) and non-syndromic cleft lip with palate (NSCLP), but they are usually grouped together and considered as the same defect with different severity (Mitchell et al, 2002); some. Individuals with NSCL/P are usually exposed to a series of problems early in life, such as difficulties in feeding and ear infections, which impose a heavy burden on both the affected families and society. There is a consensus that genes, environmental factors, and their complicated interactions contribute to the occurrence of NSCL/P (Machado et al, 2016)
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