PT  - JOURNAL ARTICLE
AU  - Annmarie Hempel
AU  - Alistair T Pagnamenta
AU  - Moira Blyth
AU  - Sahar Mansour
AU  - Vivienne McConnell
AU  - Ikuyo Kou
AU  - Shiro Ikegawa
AU  - Yoshinori Tsurusaki
AU  - Naomichi Matsumoto
AU  - Adriana Lo-Castro
AU  - Ghislaine Plessis
AU  - Beate Albrecht
AU  - Agatino Battaglia
AU  - Jenny C Taylor
AU  - Malcolm F Howard
AU  - David Keays
AU  - Aman Singh Sohal
AU  - DDD collaboration
AU  - Susanne J Kühl
AU  - Usha Kini
AU  - Alisdair McNeill
TI  - Deletions and de novo mutations of <em>SOX11</em> are associated with a neurodevelopmental disorder with features of Coffin–Siris syndrome
AID  - 10.1136/jmedgenet-2015-103393
DP  - 2016 Mar 01
TA  - Journal of Medical Genetics
PG  - 152--162
VI  - 53
IP  - 3
4099  - http://jmg.bmj.com/content/53/3/152.short
4100  - http://jmg.bmj.com/content/53/3/152.full
SO  - J Med Genet2016 Mar 01; 53
AB  - 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.