In humans, chromosomal translocations and deletions of 2q33.1 leading to SATB2 haploinsufficiency are associated with cleft palate (CP), facial dysmorphism and intellectual disability (ID).
We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans.
Haploinsufficiency of SATB2 causes cleft palate, intellectual disability with deficient speech, facial and dental abnormalities, and other variable features known collectively as SATB2-associated syndrome.
SATB2 variants should be considered in cases with psychomotor retardation alone or in any cases with Rett-like phenotypes, regardless of the typical features of SAS such as cleft palate.
One patient in this cohort has a deletion entirely within SATB2 and has a cleft palate, whereas several patients with larger deletions have a high arched palate.
We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans.
Here, we show that AEC p63 mutations affect the ability of the p63 protein to interact with special AT-rich binding protein-2 (SATB2), which has recently also been implicated in the development of cleft palate. p63 and SATB2 are co-expressed early in development in the ectoderm of the first and second branchial arches, two essential sites where signaling is required for craniofacial patterning.
Whilst there is some variation in the phenotypes of patients with 2q3 deletions all share a commonly deleted region within 2q33.1 which includes SATB2, a gene previously shown to be associated with cleft palate.
Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP.
IRF6rs2235375 single nucleotide polymorphism is associated with isolated non-syndromic cleft palate but not with cleft lip with or without palate in South Indian population.
Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate.
The disruption of IRF6 resulted in abnormal orofacial development including micrognathia and intraoral adhesions as well as tongue-palate fusion, then resulting in glossoptosis with airway obstruction and cleft palate.
Similarly, Irf6 was found to be down-regulated in the medial edge epithelia of transforming growth factor beta3-null mice, which also exhibit cleft palate.
SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance.