Craniofacial abnormalities and developmental delay in two families with overlapping 22q12.1 microdeletions involving the MN1 gene

Abstract

Deletions spanning the MN1 gene (22q12.1) have recently been proposed as playing a role in craniofacial abnormalities that include cleft palate, as mouse studies have demonstrated that Mn1 haploinsufficiency results in skull abnormalities and secondary cleft palate. We report on four patients (two families) with craniofacial abnormalities and intellectual disability with overlapping microdeletions that span the MN1 gene. Comparative genomic hybridization microarray analysis revealed a 2.76 Mb deletion in the 22q12.1 region, in three family members (Family 1), that contains the MN1 gene. In addition, a complex 22q12 rearrangement, including a 1.61 Mb deletion containing the MN1 gene and a 2.28 Mb deletion encompassing the NF2 gene, has been identified in another unrelated patient (Family 2). Based upon genotype-phenotype correlation among our patients and those previously reported with overlapping 22q12 deletions, we identified a 560 kb critical region containing the MN1 gene that is implicated in human cleft palate formation. Importantly, NF2 was also found within the 22q12 deletion region in several patients which enabled specific clinical management for neurofibromatosis 2.

Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion

“…In addition to the aforementioned syndromes, several deletions affecting chromosome 22 lead to soft palate clefts. Microdeletions of chromosome 22q12 cause cleft soft palate (Davidson et al 2012;Beck et al 2015;Breckpot et al 2015). The candidate gene in this location that is associated with palate development is the transcription factor MN1.…”

Genomic properties of structural variants and short tandem repeats that impact gene expression and complex traits in humans

“…SVs and STRs have also been associated with complex traits, though they have been studied considerably less often in GWAS than single nucleotide polymorphisms (SNPs), and the overall contribution of SVs and STRs to complex traits is not well understood (Beck et al, 2015;Brandler et al, 2018;Den Dunnen, 2017;King et al, 2015;Lupski, 2015;Malhotra and Sebat, 2012;Mirkin, 2007;Nelson et al, 2013). One difficulty with studying differences between SV classes and STRs in GWAS is that it is unknown whether variant classes are differentially tagged by SNPs on genotyping arrays.…”

An Osteoblast Origin for Craniofacial Dysplasia in Neurofibromatosis Type I

“…We find significant and robust changes in the nasal region of Nf1ob-/-mice. This pattern of deformed frontal midface region of the skull in Nf1ob-/-mice parallels the quantitative changes in the analogous structures in human NF1 craniofacial skeleton resulting in unilateral proptosis of an eye and facial asymmetry [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. NF1 patients often exhibit macrocephaly.…”

“…The incidence of malocclusion in the C57BL/6 mouse genetic background is reported to be 0.046% [24,25]. The increased frequency of malocclusion in Nf1ob-/-mice relative to control mice parallels dental abnormalities among NF1 patients [26]. In many cases of craniofacial dysplasia in NF1 a plexiform neurofibroma or optic nerve glioma is found adjacent to the bone, which may drive dysplastic changes in bone.…”