Hempel A et al. (2016), Deletions and de novo mutations of SOX11 are as...

XB-ART-51518

J Med Genet 2016 Mar 01;533:152-62. doi: 10.1136/jmedgenet-2015-103393.

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Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome.

Hempel A , Pagnamenta AT , Blyth M , Mansour S , McConnell V , Kou I , Ikegawa S , Tsurusaki Y , Matsumoto N , Lo-Castro A , Plessis G , Albrecht B , Battaglia A , Taylor JC , Howard MF , Keays D , Sohal AS , , Kühl SJ , Kini U , McNeill A .

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BACKGROUND: SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin-Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. METHODS: We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. RESULTS: We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin-Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. CONCLUSIONS: We thus propose that SOX11 deletion or mutation can present with a Coffin-Siris phenotype.

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Genes referenced: gdf5 sox11
GO keywords: head development
???displayArticle.morpholinos??? sox11 MO1

???displayArticle.disOnts??? microcephaly [+]
???displayArticle.omims??? COFFIN-SIRIS SYNDROME 1; CSS1
Phenotypes: sox11 MO KD

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	Figure1. Schematic diagram of deletions. The deletions are displayed as a custom track in UCSC genome browser with refseq genes using hg 19. The horizontal black bars represent the deletion in each patient and the two dashed vertical lines represent the smallest region of overlap. The smallest region of overlap contains only the SOX11 gene.
	Figure 2. Clinical photographs of study participants. (A). Case 4: facial photograph in top panel, photograph of hands in lower panel (note fifth finger clinodactyly). (B). Case 2: facial photograph in top panel, photograph of hands in lower panel (note fifth finger clinodactyly). (C) Case 3: facial photograph in top panel, photograph of hands in lower panel (note fifth finger clinodactyly). (D) Case 1: facial photograph in top panel. Reproduced from Lo-Castro et al.17 (E) Boy with c.150G>C (p. Lys50Asn) SOX11 mutation (case 9). Facial photograph in top panel, hand in middle panel (note fifth finger clinodactyly) and foot in lowermost panel (note broad hallux and 2–3 toe syndactyly). (F) Boy with c.87C>A (p. Cys29*) SOX11 mutation (case 10). Facial photograph in top panel, hand in middle panel (note fifth finger clinodactyly) and foot in lowermost panel (note broad hallux, 2–3 toe syndactyly and hypoplasia of nail of fifth toe). (G). Girl with c.359C>A (p. Pro120His) SOX11 mutation (case 8). Facial photograph in top panel, hand in middle panel (note fifth finger clinodactyly) and foot in lowermost panel (note broad hallux and hypoplasia of nail of fifth toe). (H) Case 7. Facial photograph in top panel, photograph of hands in lower panel (note fifth finger clinodactyly and small nails on fifth finger).
	Figure3. SOX11 variants identified in the current study. (A) Schematic diagram of SOX11 protein demonstrating location of three reported sequence variants. The p.S60P and p.Y116C variants reported by Tsurusaki et al8 are also shown, the structural effects of these mutations can be found in reference 8. (B and D) Models demonstrating alteration of SOX11 protein structure associated with the two missense variants. Green areas represent the wildtype residue while the red area indicates the structure adopted by the mutant amino acid. Both the missense variants were in the DNA binding domain of SOX11 and predicted to alter its structure, thus interfering with DNA binding. (C) Bar chart demonstrating that the twoSOX11 missense variants had reduce ability to activate the GDF5 promoter in an in vitro reporter system. The adjacent western blot confirms that the mutant proteins were stably expressed during the experiment.
	Figure 4. Sox11 knockdown leads to microcephaly in Xenopus laevis. (A) Bilateral injection of Sox11 MO results in significant smaller heads measured by the head area (white dotted circles) and the pupillary distance (red lines) compared with bilateral control MO injections. In addition, Sox11 morphants show an eye phenotype as previously described (red arrowhead; Cizelsky et al14). (B) Statistical evaluation of the measured head area. (C) Statistical evaluation of the measured pupillary distance. N, number of individual embryos analysed. ****, p0.0001. p Values were calculated by a non-parametric MannWhitney rank sum test.
	Figure 5. Expression of SOX11 in developing human brain. (A–D) Changes in SOX11 expression levels as measured by RNA-sequencing in the cerebellum, hippocampus, prefrontal cortex and striatum, respectively. Columns labelled first, second and third refer to trimesters of pregnancy. Column 10 represents the first decade of life, 20 the second decade of life and 40 the third and fourth decades. There was a significant decline in SOX11 expression levels with increasing age as assessed by the Kruskal–Wallis test (p<0.01). (E) Microarray data demonstrating that SOX11 is expression is higher in brain regions with high levels of neurogenesis (periventricular) compared with areas with low levels of neurogenesis (cerebellum, thalamus, brain stem), *p<0.01. The first two columns represent 15 weeks of gestation while the second two columns represent 21 weeks of gestation.

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Boyle, Cornelia de Lange syndrome. 2015, Pubmed