Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin–Siris syndrome-like phenotype

• Published in: Human genetics Vol. 136; no. 3; pp. 297 - 305
• Main Authors: Bramswig, Nuria C., Caluseriu, O., Lüdecke, H.-J., Bolduc, F. V., Noel, N. C. L., Wieland, T., Surowy, H. M., Christen, H.-J., Engels, H., Strom, T. M., Wieczorek, D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2017; Springer; Springer Nature B.V
• Subjects: Abnormalities, Multiple - genetics; Biomedical and Life Sciences; Biomedicine; Chromatin; DNA binding proteins; Face - abnormalities; Frameshift Mutation; Gene expression; Gene Function; Gene mutation; Genes; Genetic aspects; Genetic research; Genetics; Genotype & phenotype; Hand Deformities, Congenital - genetics; Heterozygote; Human Genetics; Humans; Infant; Intellectual disabilities; Intellectual Disability - genetics; Male; Metabolic Diseases; Micrognathism - genetics; Molecular Medicine; Mutation; Neck - abnormalities; Original Investigation; Phenotype; Transcription (Genetics); Transcription factors; Transcription Factors - genetics; Canada; Germany; TRIM8 Gene; Autism Spectrum Disorder; Coarse Facial Feature; Intellectual Disability
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-017-1757-z

Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin–Siris (CSS) and Nicolaides–Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes
ARID1B
,
SMARCA4
,
SMARCB1
,
ARID1A,
and
SMARCE1
as well as variants in the transcription factor-encoding gene
SOX11
have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the
ARID2
gene were associated with intellectual disability. In this study, we report on two individuals with private de novo
ARID2
frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the
ARID2
gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.