Disruption of the ARID1B and ADAMTS6 loci due to a t(5;6)(q12.3;q25.3) in a patient with developmental delay

• Published in: American journal of medical genetics. Part A 2014-12, Vol.164A (12), p.3126-3131
• Main Authors: Malli, Theodora, Duba, Hans-Christoph, Erdel, Martin, Marschon, Renate, Kranewitter, Wolfgang, Deutschbauer, Sabine, Kralik, Johanna, Diel, Evita, Güenther, Barbara, Mueller, Doris, Webersinke, Gerald
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; ADAM Proteins - genetics; ADAMTS Proteins; ADAMTS6; ARID1B; Chromosomes, Human, Pair 5 - genetics; Chromosomes, Human, Pair 6 - genetics; developmental delay; Developmental Disabilities - genetics; DNA-Binding Proteins - genetics; Humans; In Situ Hybridization, Fluorescence; intellectual disability; Male; Polymerase Chain Reaction; speech impairment; Transcription Factors - genetics; Translocation, Genetic - genetics
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.36738

Here, we report on a male patient with developmental delay, speech impairment, mild dysmorphic features, and borderline intellectual disability, bearing a de novo balanced t(5;6)(q11;q25.3). By combining FISH and long distance inverse PCR, we identified two genes, ADAMTS6 and ARID1B, which were disrupted at the translocation breakpoints. Due to the opposing transcriptional directions of the two genes, no fusion transcripts could be formed. ADAMTS6 on chromosome 5 encodes a zinc metalloprotease. To date, there has been no information about the substrates and the exact role of this enzyme protein. ARID1B on chromosome 6 is involved in chromatin remodeling and transcriptional activation and is known to play a role in neural development. To our knowledge, this is the fourth translocation involving ARID1B reported in association with intellectual disability. ARID1B haploinsufficiency has already been described in patients with intellectual disabilities with or without corpus callosum abnormalities, Coffin–Siris syndrome and autism (OMIM 614562 and OMIM 614556). A review of patients with ARID1B mutations reveals their broad phenotypic variability. The phenotype of the present patient is of the mildest described to date and further underscores this observation. We conclude that the most prominent and consistent clinical findings in patients with ARID1B haploinsufficiency are developmental delay, speech impairment and intellectual disability and propose that patients with unresolved genetic background and these clinical findings should be considered for ARID1B mutation screening. © 2014 Wiley Periodicals, Inc.