Further delineation of the SATB2 phenotype

Abstract

SATB2 is an evolutionarily highly conserved chromatin remodeling gene located on chromosome 2q33.1. Vertebrate animal models have shown that Satb2 has a crucial role in craniofacial patterning and osteoblast differentiation, as well as in determining the fates of neuronal projections in the developing neocortex. 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). A single patient carrying a nonsense mutation in SATB2 has been described to date. In this study, we performed trio-exome sequencing in a 3-year-old girl with CP and severely delayed speech development, and her unaffected parents. Previously, the girl had undergone conventional and molecular karyotyping (microarray analysis), as well as targeted analysis for different diseases associated with developmental delay, including Angelman syndrome, Rett syndrome and Fragile X syndrome. No diagnosis could be established. Exome sequencing revealed a de novo nonsense mutation in the SATB2 gene (c.715C>T; p.R239*). The identification of a second patient carrying a de novo nonsense mutation in SATB2 confirms that this gene is essential for normal craniofacial patterning and cognitive development. Based on our data and the literature published so far, we propose a new clinically recognizable syndrome - the SATB2-associated syndrome (SAS). SAS is likely to be underdiagnosed and should be considered in children with ID, severe speech delay, cleft or high-arched palate and abnormal dentition with crowded and irregularly shaped teeth.

Figure 1

Synopsis of the patients carrying microdeletions restricted to SATB2 published so far.^, Extent and position of the deletions are derived from the respective original articles. Exons are shown in real relative size (according to NM_001172517.1), whereas intronic areas are standardized and sized down. Larger deletions encompassing neighboring genes and translocations disrupting SATB2 are not shown. A comprehensive overview of larger deletions encompassing the SATB2 locus can be found in Balasubramanian et al. (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, 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). Indicated in yellow are the functional domains of SATB2, according to the Uniprot database. There are a dimerization domain, two CUT domains and one homeodomain (Hox), which constitute crucial DNA-binding motifs. A full color version of this figure is available at the European Journal of Human Genetics journal online.

Figure 2

(a, b) Facial features of the patient at the age of 2 9/12 years. Note the hypotonic face with pronounced salivation. The girl displays hypertelorism, downslanting palpebral fissures, long eyelashes and a slightly upturned nose with a broad tip. She has micrognathia, a long and poorly modulated philtrum, and the ears are low set and dorsally rotated. (c) Irregular shape and positioning of the teeth. Consent of the parents for publishing the pictures was obtained.