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.
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).
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.
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.
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.
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.
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.
While single heterozygous mice are normal, double heterozygous embryos (Irf6 <sup>+/-</sup> ; Twist1 <sup>+/-</sup> ) can have severe mandibular hypoplasia that leads to agnathia and cleft palate at birth.
Mutations in the interferon regulatory factor 6 (IRF6) gene are known to cause van der Woude syndrome (VWS), a common syndromic form of oro-facial clefting characterized by the familial occurrence of mixed clefting (cleft lip with or without a cleft palate and cleft palate alone in the same family) and lower lip pits.
Mutations in IRF6 cause Van der Woude syndrome (VWS), one of the most common syndromes associated with cleft lip (CL) with or without cleft palate (CP).
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.
Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without 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.
Recently, we have demonstrated that mice homozygous for a mutation in Irf6 exhibit abnormalities of epithelial differentiation that results in cleft palate as a consequence of adhesion between the palatal shelves and the tongue.
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.