Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings

The gene encoding the AT‐rich interaction domain‐containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non‐specific ID to Coffin–Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole‐exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence. © 2015 Wiley Periodicals, Inc.

[1]  C. Bruno,et al.  Paternal germline mosaicism in collagen VI related myopathies. , 2015, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[2]  J. Vermeesch,et al.  Coffin–Siris and Nicolaides–Baraitser syndromes are a common well recognizable cause of intellectual disability , 2015, Brain and Development.

[3]  D. Valle,et al.  New Tools for Mendelian Disease Gene Identification: PhenoDB Variant Analysis Module; and GeneMatcher, a Web‐Based Tool for Linking Investigators with an Interest in the Same Gene , 2015, Human mutation.

[4]  R. Hopkin,et al.  A novel dominant COL11A1 mutation resulting in a severe skeletal dysplasia , 2014, American journal of medical genetics. Part A.

[5]  J. Clayton-Smith,et al.  The ARID1B phenotype: What we have learned so far , 2014, American journal of medical genetics. Part C, Seminars in medical genetics.

[6]  J. Biegel,et al.  SWI/SNF chromatin remodeling complexes and cancer , 2014, American journal of medical genetics. Part C, Seminars in medical genetics.

[7]  K. Kutsche,et al.  Evidence of Germline Mosaicism for a Novel BCOR Mutation in Two Indian Sisters with Oculo-Facio-Cardio-Dental Syndrome , 2014, Molecular Syndromology.

[8]  N. Matsumoto,et al.  Coffin–Siris syndrome is a SWI/SNF complex disorder , 2014, Clinical genetics.

[9]  K. Devriendt,et al.  A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. , 2013, Human molecular genetics.

[10]  A. V. Vulto-van Silfhout,et al.  Coffin–Siris Syndrome and the BAF Complex: Genotype–Phenotype Study in 63 Patients , 2013, Human mutation.

[11]  Wei Wu,et al.  From neural development to cognition: unexpected roles for chromatin , 2013, Nature Reviews Genetics.

[12]  G. Crabtree,et al.  Reversible Disruption of mSWI/SNF (BAF) Complexes by the SS18-SSX Oncogenic Fusion in Synovial Sarcoma , 2013, Cell.

[13]  S. Ferrari,et al.  A novel de novo missense mutation in TP63 underlying germline mosaicism in AEC syndrome: Implications for recurrence risk and prenatal diagnosis , 2012, American journal of medical genetics. Part A.

[14]  Christian Gilissen,et al.  Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome , 2012, Nature Genetics.

[15]  E. Schröck,et al.  Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. , 2012, American journal of human genetics.

[16]  H. Lomelí,et al.  Dynamics of expression of ARID1A and ARID1B subunits in mouse embryos and in cells during the cell cycle , 2011, Cell and Tissue Research.

[17]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[18]  G. Crabtree,et al.  ATP-dependent chromatin remodeling: genetics, genomics and mechanisms , 2011, Cell Research.

[19]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[20]  Marcos J. Araúzo-Bravo,et al.  Chromatin-Remodeling Components of the BAF Complex Facilitate Reprogramming , 2010, Cell.

[21]  J. Chiang,et al.  Mutation analysis of the APC gene in Taiwanese FAP families: low incidence of APC germline mutation in a distinct subgroup of FAP families , 2010, Familial Cancer.

[22]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[23]  R. Aebersold,et al.  An Essential Switch in Subunit Composition of a Chromatin Remodeling Complex during Neural Development , 2007, Neuron.

[24]  L. Biesecker,et al.  Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR , 2004, Nature Genetics.

[25]  M. Cleary,et al.  Novel SWI/SNF Chromatin-Remodeling Complexes Contain a Mixed-Lineage Leukemia Chromosomal Translocation Partner , 2003, Molecular and Cellular Biology.

[26]  Hans Clevers,et al.  Cloning and characterization of hELD/OSA1, a novel BRG1 interacting protein. , 2002, The Biochemical journal.

[27]  M. Russell,et al.  Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. , 1995, Journal of medical genetics.

[28]  Kurt Hirschhorn,et al.  Familial de Lange syndrome , 1971, Clinical genetics.

[29]  C. Roberts,et al.  ARID1A mutations in cancer: another epigenetic tumor suppressor? , 2013, Cancer discovery.