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. 2012 Apr;2(6):237-244.
doi: 10.1159/000337323. Epub 2012 Mar 16.

In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome

D Wolff  1 , S Endele, S Azzarello-Burri, J Hoyer, M Zweier, I Schanze, B Schmitt, A Rauch, A Reis, C Zweier
Affiliations

In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome

D Wolff et al. Mol Syndromol. 2012 Apr.

Abstract

Using high-resolution molecular karyotyping with SNP arrays to identify candidate genes for etiologically unexplained intellectual disability, we identified a 32-kb de novo in-frame deletion of the C-terminal helicase domain of the SMARCA2 gene in a patient with severe intellectual disability, epilepsy, sparse hair, prominent joints, and distinct facial anomalies. Sequencing of the gene in patients with a similar phenotype revealed de novo missense mutations in this domain in 2 further patients, pointing to a crucial role of the SMARCA2 C-terminal helicase domain. The clinical features observed in all 3 patients are typical of Nicolaides-Baraitser syndrome, an only rarely reported syndrome with mainly moderate to severe intellectual disability. Notably, one of our patients with a p.Gly1132Asp mutation showed typical morphological features but an exceptional good development with borderline overall IQ and learning difficulties, thus expanding the phenotypic spectrum of Nicolaides-Baraitser syndrome.

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Figures

Fig. 1
Fig. 1
Phenotypes of 3 patients with defects in SMARCA2. A, B Patient 1 at the age of 21 months. C–F Facial gestalt, hand and foot of patient 1 at the age of 3 years and 7 months. G, H Patient 2 at the age of 3 years and 6 months. I–L Facial gestalt, hand and foot of patient 2 at the age of 8 years. M–R Scalp hair, knees, hand from in- and outside, and foot of patient 3 at the age of 9 years.
Fig. 2
Fig. 2
Identified defects in SMARCA2. A Affymetrix 6.0 Array data of patient 1 and his parents showing an intragenic de novo deletion of 32 kb within the SMARCA2 gene at 9p24.3. The first and last deleted probes as indicated by the array were SNP_A-8705668 (hg18: chr9: 2,079,813) and SNP_A-8601038 (hg18: chr9: 2,111,371). B Conservation of the amino acid positions 1132 and 1188 affected by the missense mutations found in patients 2 and 3. C Schematic drawing of the SMARCA2 gene with localization of the deletion and the 2 missense mutations. Exons are color-coded for encoded domains (according to PROSITE, http://prosite.expasy.org/). HSA: helicase-SANT-associated domain; HEL-ATP-bind: helicase domain with ATP binding function; Hel-C-term: C-terminal helicase domain; Bromo: bromodomain; exon 1 and parts of exon 34 are non-coding (gray).
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