Heterozygous nonsense mutationSATB2 associated with cleft palate, osteoporosis, and cognitive defects

Abstract

Studies of human chromosomal aberrations and knockout (KO) mice have suggested SATB2 as a candidate gene for a human malformation syndrome of craniofacial patterning and brain development. Of 59 unrelated patients with craniofacial dysmorphism, with or without mental retardation, one 36-year-old man had a nonsynonymous mutation in SATB2. The affected individual exhibited craniofacial dysmorphisms including cleft palate, generalized osteoporosis, profound mental retardation, epilepsy and a jovial personality. He carries a de novo germline nonsense mutation (c.715C>T, p.R239X) in the exon 6 of SATB2. Expression studies showed that the mutant RNA was stable, expected to produce a truncated protein predicted to retain its dimerization domain and exert a dominant negative effect. This new syndrome is the first determined to result from mutation of a gene within the family that encodes nuclear matrix-attachment region (MAR) proteins.

Further delineation of the SATB2 phenotype

“…A comprehensive overview of larger deletions encompassing the SATB2 locus can be found in Balasubramanian et al 10 (cave: new genes have been annotated to the 2q33.1 region, which are not listed in that publication). Only one de novo nonsense mutation has been described before, 18 affecting the exact same nucleotide position as the one described in this report (blue arrow). In addition, a probably pathogenic missense mutation has been reported (grey arrow).…”

“…10,17 Only one patient carrying a nonsense mutation in SATB2 has been reported in the literature to date. 18 This individual was identified by screening of 59 patients with craniofacial dysmorphisms with or without ID. Recently, a patient carrying a missense mutation in SATB2 which was judged as probably damaging was identified in screening a cohort of patients with ID for de novo variants.…”

PDGFRa mutations in humans with isolated cleft palate

“…However, they still contribute to a small PDGFRa mutations in isolated cleft palate S Rattanasopha et al fraction, approximately 7% of patients. 13,14 To better understand the genetic factors contributing to CP, more susceptible genes are needed to be identified. PDGFRa was previously suggested to have a role in diaphragmatic hernia 15 and total anomalous pulmonary venous return (TAPVR).…”

Characterization of the first intragenic SATB2 duplication in a girl with intellectual disability, nearly absent speech and suspected hypodontia

“…[6][7][8][9][10] The patient presented with ID, nearly absent speech and suspected hypodontia, the characteristic features of SAS. By molecular genetic investigations we were able to confirm a tandem duplication of exon 3 with different coexpressed transcripts of SATB2.…”

“…[1][2][3][4][5][6] Recently, Döcker et al 7 provided a summary of patients harboring an alteration of this gene in this Journal. They delineated the SATB2 phenotype by comparing four patients with deletions restricted to SATB2, 8,9 two patients with the same heterozygous nonsense variant (c.715C4T, p.R239*) 7,10 and preliminary information on the patient of this report with an intragenic SATB2 duplication, presented at that time in abstract form. 11 They proposed a clinically recognizable SAS (SATB2-associated syndrome), characterized by severe intellectual disability (ID) with no or only limited speech, behavioral problems and abnormalities in craniofacial patterning, namely micrognathia, cleft or high-arched palate, and abnormalities of the teeth such as oligodontia and/or misshaped and crowded teeth.…”