Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes.

Hum Genet 2015 Jun 28;134(6):553-68. Epub 2015 Feb 28.

Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany,

Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann-Steiner, Kabuki, and Adams-Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers.

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-015-1535-8DOI Listing
June 2015
71 Reads

Publication Analysis

Top Keywords

differential diagnoses
12
baf complex
8
tentative diagnosis
8
caused mutations
8
individuals tentative
8
diagnosis css
8
ncbrs causative
8
css ncbrs
8
kabuki adams-oliver
4
adams-oliver syndromes
4
including wiedemann-steiner
4
disclosed overlapping
4
overlapping differential
4
diagnoses including
4
wiedemann-steiner kabuki
4
addition causative
4
identified grin2a
4
grin2a shank3
4
shank3 trio-based
4
mutations identified
4

Similar Publications