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Cell Lines Or Lymphocytes Collected from Blood Via Trizol HDAC4 in Each of These Cases Revealed De Novo Mutations

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Cell Lines Or Lymphocytes Collected from Blood Via Trizol HDAC4 in Each of These Cases Revealed De Novo Mutations View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ARTICLE Haploinsufficiency of HDAC4 Causes Brachydactyly Mental Retardation Syndrome, with Brachydactyly Type E, Developmental Delays, and Behavioral Problems Stephen R. Williams,1 Micheala A. Aldred,3 Vazken M. Der Kaloustian,4,6 Fahed Halal,5 Gordon Gowans,7 D. Ross McLeod,8 Sara Zondag,9 Helga V. Toriello,9 R. Ellen Magenis,10 and Sarah H. Elsea1,2,* Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candi- date genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, À/À neurological, and cardiac development. Reportedly, Hdac4 mice have severe bone malformations resulting from premature ossifica- tion of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome. Introduction Refining the critical region for deletion 2q37 syndrome has proven difficult because of poor genotype:phenotype Chromosome deletions involving the 2q37 region result correlation and a paucity of interstitial deletions that in brachydactyly mental retardation syndrome (BDMR would help define minimal overlapping candidate regions. [MIM 600430]), also known as Albright hereditary osteo- To date, the critical region for this syndrome has not been dystrophy-like syndrome (AHO-like). BDMR is a complex clearly defined, and a variety of phenotypes have been disorder that presents with a spectrum of clinical features, mapped to the 2q37.1/2qter region.2 Variable expres- including developmental delay, obesity, autism spectrum sivity and reduced penetrance for most major features disorder, and craniofacial and skeletal abnormalities, complicate genotype:phenotype correlations in this syn- including brachydactyly type E in approximately 50% of drome and further impair diagnosis. cases.1,2 Cardiac defects are reported in ~20% of cases,1 In a study of 52 individuals referred for a phenotype and behavioral problems and neurological anomalies are consistent with Smith-Magenis syndrome (SMS) for whom common.3–5 The deletion 2q37 syndrome phenotype no 17p11.2 deletion or RAI1 (MIM 607642) mutation consists of a variety of findings that overlap with other could be found, we identified by whole-genome array syndromes, including Smith-Magenis (SMS [MIM comparative genomic hybridization (aCGH) several copy 182290]), Prader-Willi (PWS [MIM 176270]), Angelman number variants responsible for the SMS-like phenotypes (AS [MIM 105830]), and fragile-X (FRAX [MIM 300624]) observed in these individuals.6 Interestingly, we identified syndromes. two cases that carried overlapping deletions of the 2q37 Approximately 100 individuals have been reported region.6 After a literature review, we discovered that the with a deletion involving the chromosome 2q37 region.2 phenotypic overlap between these two distinct syndromes Genotype:phenotype correlations have been attempted was striking. Utilizing this unique aCGH data set and addi- in the past but have failed to identify a single gene that tional cases, we refined the critical region for BDMR, may contribute to the core findings observed in BDMR. reducing the likely candidates to a single gene, HDAC4 1Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; 2Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; 3Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; 4Department of Pediatrics, The Montreal Children’s Hospital, McGill University, Montreal, Quebec H3H 1P3, Canada; 5Division of Medical Genetics, The Montreal Children’s Hospital, McGill University, Montreal, Quebec H3H 1P3, Canada; 6Department of Human Genetics, McGill University, Montreal, Quebec H3H 1P3, Canada; 7Weisskopf Child Evaluation Center, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; 8Department of Medical Genetics, University of Calgary, Calgary, Alberta T2N 4N1, Canada; 9Genetic Services, Spectrum Health, Grand Rapids, MI 49503, USA; 10Department of Genetics, Oregon Health & Science University, Portland, OR 97239, USA *Correspondence: [email protected] DOI 10.1016/j.ajhg.2010.07.011. Ó2010 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 87, 219–228, August 13, 2010 219 (MIM 605314). Given the apparent phenotypic overlap the genomic extent of HDAC4 (Table S3). Breakpoints outside of between SMS and BDMR, we then investigated more the HDAC4 gene were defined with Illumina CNV370 single closely the specific phenotypes in our cohorts with nucleotide polymorphism arrays and Beadstudio software to iden- Smith-Magenis syndrome-like and/or AHO-like features tify copy number changes. and identified two subjects who lacked a 2q37 deletion but had striking phenotypic overlap with known 2q37 Quantitative Real-Time PCR deletion cases. Sequencing of the coding region of RNA was isolated from cultured patient and control lymphoblas- toid cell lines or lymphocytes collected from blood via Trizol HDAC4 in each of these cases revealed de novo mutations. (Invitrogen, Carlsbad, CA) according to standard protocols. All Studies show that HDAC4 (histone deacetylase 4) is critical cell lines were cultured for the same period of time to the same 7 for proper skeletogenesis and chondrogenesis, as well as cell density, and all samples were processed in the same manner. 8 neuronal survival. Taking into consideration the overlap- Quantitative reverse transcriptase real-time PCR was performed as ping deletion data and de novo mutations presented here, previously described11 via Taqman probes (Applied Biosystems, we assert that haploinsufficiency of HDAC4 results in the Foster City, CA) for GAPDH (MIM 138400, internal control), brachydactyly mental retardation syndrome. HDAC4, or RAI1. Control RNAs for real-time PCR assays came from ‘‘like’’samples, i.e., whole blood or cultured cells, as described, and at least two different control samples were analyzed for each Material and Methods expression assay to ensure expression data were consistent. Subject Ascertainment Results Subjects were not formally recruited. Samples and medical records were ascertained after informed consent was obtained by referral based on suspicion of Smith-Magenis syndrome or AHO-like As listed and described in Table 1, common features of features. Subjects were referred to the S.H.E. laboratory for molec- BDMR include mild facial dysmorphism, congenital heart ular evaluation of SMS at Michigan State University or Virginia defects, distinct brachydactyly type E (BDE), intellectual Commonwealth University or to the M.A.A. laboratory at the disabilities, developmental delay, seizures, autism spec- Cleveland Clinic for AHO-like phenotype. Samples and medical trum disorder, and obesity.1,2 By utilizing recent studies records were collected in accordance with Institutional Review of SMS-like6 and known deletion 2q37 subjects,1 we were Board-approved protocols from the appropriate institution. able to make genotype:phenotype correlations allowing Peripheral blood was collected, and DNA and metaphase chromo- refinement of the critical region for BDMR to ~chr2: somes were prepared according to standard methods. Phenotypic 239,639,900-240,938,547 within the 2q37.3 band, information was collected from medical records, geneticist reports, including the HDAC4 gene (Figure 1). and patient photos. Refinement of the BDMR Critical Region Genomic DNA Sequence Analysis Because the deletions we identified map to a small overlap- Total DNA was isolated from cultured peripheral white blood ping region within the 2q37.3 band,1,6 we were able to cells with the QIAamp DNA Minikit (QIAGEN, Hilden, Germany). PCR was performed with intronic primers from the HDAC4 gene narrow the critical region to ~200 kb region including 0 0 HDAC4 generated with Primer3 (v. 0.4.0), which flank both the 5 and 3 (Figure 1), with SMS272 critical to this analysis re- regions of each HDAC4 exon (Table S1 available online). PCR
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