Further delineation of the SATB2 phenotype

Döcker, Dennis; Schubach, Max; Menzel, M.; Munz, Marita; Spaich, Christiane; Biskup, Saskia; Bartholdi, Deborah

doi:10.1038/ejhg.2013.280

Cited by 74 publications

(101 citation statements)

References 41 publications

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“…[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.…”

Section: Resultsmentioning

confidence: 99%

“…[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.…”

Section: Introductionmentioning

confidence: 99%

“…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. 7 In the meantime, Rainger et al 12 have published about three unrelated individuals with translocation breakpoints 3 0 of SATB2 and a comparable phenotype to that in patients with SATB2 mutations, suggesting the action of cis-regulatory elements in this region as a further pathomechanism. The patient of this report represents the first case of an intragenic SATB2 duplication and has not been described with sufficient clinical and molecular data so far.…”

Section: Introductionmentioning

confidence: 99%

“…The patient of this report represents the first case of an intragenic SATB2 duplication and has not been described with sufficient clinical and molecular data so far. Therefore, in reaction to the article by Döcker et al, 7 we would like to add a detailed description of the patient's phenotype and genotype, correcting hereby the information given in the paper by Döcker et al, 7 and adding to the knowledge on molecular mechanisms leading to SAS.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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SATB2, a gene encoding a highly conserved DNA-binding protein, is known to have an important role in craniofacial and neuronal development. Only a few patients with SATB2 variants have been described so far. Recently, Dö cker et al provided a summary of these patients and delineated the SAS (SATB2-associated syndrome). We here report on a girl with intellectual disability, nearly absent speech and suspected hypodontia who was shown to carry an intragenic SATB2 tandem duplication hypothesized to lead to haploinsufficiency of SATB2. Preliminary information on this patient had already been included in the article by Dö cker et al. We want to give a detailed description of the patient's phenotype and genotype, providing further insight into the spectrum of the molecular mechanisms leading to SAS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…The diagnostic pipeline was as previously reported. 8 Exome sequencing of leukocyte DNA revealed a de novo heterozygous variant in the PTPN11 gene (c.1529A4G; p.(Gln510Arg); according to LRG_614, NG_007459.1, NM_002834.3 and ENST00000351677). Both parents did not carry this variant.…”

Section: Methods and Resultsmentioning

confidence: 99%

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

et al. 2014

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Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactylythus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A4G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (4100 Â coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (41000 Â coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G4A; p. (Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

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Intragenic duplication—A novel causative mechanism for SATB2‐associated syndrome

Liedén

Kvarnung

Nilssson

et al. 2014

American J of Med Genetics Pt A

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Previous studies have shown that genetic aberrations involving the special AT-rich sequence-binding protein 2 (SATB2) gene result in a variable phenotype of syndromic intellectual disability. Although only a small number of patients have been described, there is already considerable variation in regard to the underlying molecular mechanism spanning from structural variation to point mutations. We here describe a male patient with intellectual disability, speech and language impairment, cleft palate, malformed teeth, and oligodontia. Array CGH analysis identified a small intragenic duplication in the SATB2 gene that included three coding exons. The result was confirmed by multiplex ligation-dependent probe amplification and low coverage whole genome mate pair sequencing. WGS breakpoint analysis directly confirmed the duplication as intragenic. This is the first reported patient with an intragenic duplication in SATB2 in combination with a phenotype that is highly similar to previously described patients with small deletions or point mutations of the same gene. Our findings expand the spectra of SATB2 mutations and confirm the presence of a distinct SATB2-phenotype with severe ID and speech impairment, cleft palate and/or high arched palate, and abnormalities of the teeth. For patients that present with this clinical picture, a high-resolution exon targeted array CGH and/or WGS, in addition to sequencing of SATB2, should be considered.

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Further delineation of the SATB2 phenotype

Cited by 74 publications

References 41 publications

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

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

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

Intragenic duplication—A novel causative mechanism for SATB2‐associated syndrome

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