Haploinsufficiency of ARID1B, a Member of the SWI/SNF-A Chromatin-Remodeling Complex, Is a Frequent Cause of Intellectual Disability
2012; Elsevier BV; Volume: 90; Issue: 3 Linguagem: Inglês
10.1016/j.ajhg.2012.02.007
ISSN1537-6605
AutoresJuliane Hoyer, Arif B. Ekici, Sabine Endele, Bernt Popp, Christiane Zweier, Antje Wiesener, Eva Wohlleber, Andreas Dufke, Eva Rossier, Corinna Petsch, Markus Zweier, Ina Göhring, Alexander M. Zink, Gudrun Rappold, Evelin Schröck, Dagmar Wieczorek, Olaf Rieß, Hartmut Engels, Anita Rauch, André Reis,
Tópico(s)Genomics and Chromatin Dynamics
ResumoIntellectual disability (ID) is a clinically and genetically heterogeneous common condition that remains etiologically unresolved in the majority of cases. Although several hundred diseased genes have been identified in X-linked, autosomal-recessive, or syndromic types of ID, the establishment of an etiological basis remains a difficult task in unspecific, sporadic cases. Just recently, de novo mutations in SYNGAP1, STXBP1, MEF2C, and GRIN2B were reported as relatively common causes of ID in such individuals. On the basis of a patient with severe ID and a 2.5 Mb microdeletion including ARID1B in chromosomal region 6q25, we performed mutational analysis in 887 unselected patients with unexplained ID. In this cohort, we found eight (0.9%) additional de novo nonsense or frameshift mutations predicted to cause haploinsufficiency. Our findings indicate that haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a common cause of ID, and they add to the growing evidence that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders. Intellectual disability (ID) is a clinically and genetically heterogeneous common condition that remains etiologically unresolved in the majority of cases. Although several hundred diseased genes have been identified in X-linked, autosomal-recessive, or syndromic types of ID, the establishment of an etiological basis remains a difficult task in unspecific, sporadic cases. Just recently, de novo mutations in SYNGAP1, STXBP1, MEF2C, and GRIN2B were reported as relatively common causes of ID in such individuals. On the basis of a patient with severe ID and a 2.5 Mb microdeletion including ARID1B in chromosomal region 6q25, we performed mutational analysis in 887 unselected patients with unexplained ID. In this cohort, we found eight (0.9%) additional de novo nonsense or frameshift mutations predicted to cause haploinsufficiency. Our findings indicate that haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a common cause of ID, and they add to the growing evidence that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders. Intellectual disability (ID) is a severely incapacitating condition that imposes a significant burden on affected individuals and their families. The incidence is estimated at 2%–3%, and severe forms (intelligence quotient [IQ] < 50) account for about 0.5% of all newborns. It is now accepted, at least in developed countries, that the vast majority of cases are of genetic origin.1Ropers H.H. Genetics of early onset cognitive impairment.Annu. Rev. Genomics Hum. Genet. 2010; 11: 161-187Crossref PubMed Scopus (265) Google Scholar Some 10% of affected boys are estimated to have an X-linked condition, and in about 80% of X-linked families, the underlying genetic defect has now been uncovered through systematic sequencing of all X-chromosomal coding segments.1Ropers H.H. Genetics of early onset cognitive impairment.Annu. Rev. Genomics Hum. Genet. 2010; 11: 161-187Crossref PubMed Scopus (265) Google Scholar, 2Tarpey P.S. Smith R. Pleasance E. Whibley A. Edkins S. Hardy C. O'Meara S. Latimer C. Dicks E. Menzies A. et al.A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.Nat. Genet. 2009; 41: 535-543Crossref PubMed Scopus (467) Google Scholar Autosomal-recessive forms are amenable to positional cloning in consanguineous families, and this strategy has recently led to the identification of an important number of genes harboring recessive mutations.3Abou Jamra R. Philippe O. Raas-Rothschild A. Eck S.H. Graf E. Buchert R. Borck G. Ekici A. Brockschmidt F.F. Nöthen M.M. et al.Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.Am. J. Hum. Genet. 2011; 88: 788-795Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 4Najmabadi H. Hu H. Garshasbi M. Zemojtel T. Abedini S.S. Chen W. Hosseini M. Behjati F. Haas S. Jamali P. et al.Deep sequencing reveals 50 novel genes for recessive cognitive disorders.Nature. 2011; 478: 57-63Crossref PubMed Scopus (690) Google Scholar Investigating sporadic cases from nonconsanguineous couples is more difficult, but the discovery of several genes involved has been enabled by either synaptic candidate-gene approaches or the de novo occurrence of copy-number variants (CNVs) or chromosomal translocations.5Endele S. Rosenberger G. Geider K. Popp B. Tamer C. Stefanova I. Milh M. Kortüm F. Fritsch A. Pientka F.K. et al.Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.Nat. Genet. 2010; 42: 1021-1026Crossref PubMed Scopus (375) Google Scholar, 6Hamdan F.F. Gauthier J. Spiegelman D. Noreau A. Yang Y. Pellerin S. Dobrzeniecka S. Côté M. Perreau-Linck E. Carmant L. et al.Synapse to Disease GroupMutations in SYNGAP1 in autosomal nonsyndromic mental retardation.N. Engl. J. Med. 2009; 360: 599-605Crossref PubMed Scopus (220) Google Scholar, 7Hamdan F.F. Piton A. Gauthier J. Lortie A. Dubeau F. Dobrzeniecka S. Spiegelman D. Noreau A. Pellerin S. Côté M. et al.De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.Ann. Neurol. 2009; 65: 748-753Crossref PubMed Scopus (124) Google Scholar, 8Zweier M. Gregor A. Zweier C. Engels H. Sticht H. Wohlleber E. Bijlsma E.K. Holder S.E. Zenker M. Rossier E. et al.Cornelia KrausMutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.Hum. Mutat. 2010; 31: 722-733Crossref PubMed Scopus (125) Google Scholar Whole-exome sequencing in 10 and 20 trios confirmed the power of this technique to identify ID-associated genes, and several studies proposed that many sporadic cases might arise from de novo mutations.9O'Roak B.J. Deriziotis P. Lee C. Vives L. Schwartz J.J. Girirajan S. Karakoc E. Mackenzie A.P. Ng S.B. Baker C. et al.Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.Nat. Genet. 2011; 43: 585-589Crossref PubMed Scopus (886) Google Scholar, 10Vissers L.E. de Ligt J. Gilissen C. Janssen I. Steehouwer M. de Vries P. van Lier B. Arts P. Wieskamp N. del Rosario M. et al.A de novo paradigm for mental retardation.Nat. Genet. 2010; 42: 1109-1112Crossref PubMed Scopus (624) Google Scholar Despite important advances in identifying the underlying genes, some 50% of all cases and the vast majority of unspecific patients remain undiagnosed.11Rauch A. Hoyer J. Guth S. Zweier C. Kraus C. Becker C. Zenker M. Hüffmeier U. Thiel C. Rüschendorf F. et al.Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation.Am. J. Med. Genet. A. 2006; 140: 2063-2074Crossref PubMed Scopus (309) Google Scholar This is probably a result of the enormous locus heterogeneity because most genes with autosomal-dominant mutations only account for a few cases each. The German Mental Retardation Network (MRNET) aims to systematically uncover the genetic basis of ID. Over several years, we recruited from eight different medical-genetics centers a large study group of affected individuals mostly of German origin. The study was approved by all institutional review boards of the participating institutions, and written informed consent was obtained from all participants or their legal guardians. We screened 1,986 of the individuals with array-based molecular karyotyping by using high-resolution platforms. In one male infant, we identified a 2.5 Mb deletion containing five genes in chromosomal region 6q25.3 (Figure 1) by using the high-resolution Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, California) and the Affymetrix Genotyping Console Software (version 3.0.2). Segregation analysis of both parents revealed a de novo origin of the deletion. The familial relationship was confirmed. Because the phenotype of our patient resembled that of the patients with larger deletions,12 we hypothesized that one of the five deleted genes would show haploinsufficiency and would represent a phenocritical gene responsible for the ID. Using Sanger sequencing, we screened all five genes from this region, including TFB1M (MIM 607033), NOX3 (MIM 607105), and three brain-expressed genes, TIAM2 (MIM 604709), CLDN20, and ARID1B, for point mutations in 121 individuals with moderate to severe ID without a known genetic cause; these individuals were from the Erlangen subgroup of the German Intellectual Disability Network (MRNET). Microarray analyses for CNVs >200 kb had been previously performed in 82 (68%) of the individuals, and no obvious pathogenic CNV was found. For sequencing, we used Applied Biosystems (ABI) BigDye Terminator chemistry and purification with Agencourt AMPure and CleanSEQ kits (Beckman-Coulter) on an ABI 3730 sequencer with Sequencing Analysis v.3.6.1 (Applied Biosystems) and Sequencher 4.9 (Gene Codes Corporation) software packages. Although no mutation was detected in TFB1M, NOX3, TIAM2, or CLDN20, we identified a c.3919C>T (p.Gln1307∗) nonsense mutation in exon 16 of ARID1B in patient 3 and an 11 bp deletion in exon 20 of ARID1B (NM_020732.3) in patient 4; the latter mutation (c.6463_6473del [p.Ser2155Leufs∗33]) lead to a frameshift and a premature termination codon after 33 residues. We used original, nonamplified DNA samples for independent PCR and bidirectional sequencing to confirm the mutations. In addition, we reanalyzed the genomic region of ARID1B for CNVs T (p.Gln1307∗)c.6463_6473del (p.Ser2155Leufs∗33)c.3304C>T (p.Arg1102∗)c.3323_3324delAA (p.Lys1108Argfs∗9)c.4110G>A (p.Arg1338Argfs∗76)c.4038T>A (p.Tyr1346∗)c.1114 dupC (p.Arg372Profs∗163)Inheritancede novode novode novode novode novode novode novode novode novode novode novoSex2 F, 2 M6 F, 2 MFFMMFFFMMAge at last follow-up examination10–33 months3–46 years3 years, 3 months4 years, 11 months3 years, 5 months7 years, 3 months12 years, 8 months4 years6 years, 3 months17 years20 yearsBirth parameters (weight, length, OFC)3 ≤ 3rd ct 2 ≤ 5th ct 3 < 3rd ct3/7 ≤ 10th ct 5/6 ≤ 10th ct 5 ≤ 10th ct50th ct 3rd−10th ct 50th−75th ct25th ct 50th ct 25th ct50th ct 25th ct 25th ct50th ct 50th ct 50th ct25th ct 25th ct 50th ct3rd−10th ct 50th ct 3rd−10th ct50th−75th ct >97th ct 75th ct10th−50th ct 50th ct 10th−50th ct10th ct 50th ct 50th ctLength and/or height and OFC2/4 < 3rd ct 4/4 < 3rd ct7/7 ≤ 5th ct 1/5 < 3rd ct10th ct 10th−25th ct3rd−10th ct <3rd ct3rd−10th ct 50th ct<3rd ct 25th−50th ct 97th ct<3rd ct 5 years and two-word sentences at 12 yearsat age of 24 months, corresponding to age of 17 monthssingle wordsshort sentences and sufficient working vocabularydelayedAge of walking1/4 at 23 months1/1 at 30 months28 months24 months20 months+27 months24 months24 months18 months20 monthsMuscular hypotonia2/47/7+++++++––MRI scan anomaly2/3 (2 with ACC)4/5 with ACC or HCCretrocerebellar cystdelayed myelinationNA––NAasymmetric calvariaNA–Seizures1/43/7––––+∗∗–+∗∗+–Hearing loss4/4?––––+ (unilateral)––––Heart malformation1/4 (ASD)?–+–+ (ASD)–––––Cleft palate0/4 with cleft palate and 2/4 with palatal anomalies?–– and high palate–++–– and high palate––Abnormal shape of head3/4 with plagiocephaly5/5 with low hairlineplagiocephaly and frontal bossingplagiocephaly and frontal bossingprominent forehead–brachycephaly and low foreheadfrontal bossinglow forehead–brachycephalyLow-set and/or posteriorly rotated ears4/42/2+++–+++++Abnormally shaped ears2/4?+++++–+–+Downslanting palpebral fissures2/4?+–+++––––Strabism+2++–+–––––Bulbous nasal tip3/33/3++–++/–+/−+––Thin upper lip2/43/4–+++++––+Teeth anomalies??–small and pointedpointedsmallfirst teeth small and widely spaced–smallmalocclusion and delayed second dentitionNARetro/micrognathia2/3?++–––+-+–Hand and feet anomalies1/4 with clinodactyly and 0/4 with single palmar crease?–single palmar creases and brachydactyly Vbrachydactylysingle palmar creases, sandal gaps, and hypoplastic nailssandal gaps, clinodactyly V, and hypoplastic toe nails Vlong toes––single palmar creases, clinodactyly V, deep set thumbs, and Hallux valgusOther abnormalities2/4 with retinal anomalies; 1/4 with genitourinary anomaly5/7 with AuSD or autistic traits, 4 with myopia/hypermetropia, 1 with cataracts, 4 with hypertrichosis, and 5 with feeding problemsclitoris hypertrophy and long philtrumataxic gait, sparse hair, sacral dimple, and three hemangiomasallergy, recurrent infections, autistic features, and aggressioncryptorchism and myopiaallergy, myopia, megaureter, wide mouth, dry hair, and hypothyreosishypertrichosis and myopiahypertrichosismyopia, skin hypopigmentation, and hypertelorismunilateral myopia, blocked nasolacrimal duct, dermoid cyst, atlanto/occipital abnormalities, discreet rhizomelic shortening of arms and legs, scoliosis, and cryptorchismThe following abbreviations are used: N, number of patients; F, female; M, male; ct, percentile; OFC, occipital-frontal circumference; IQ, intelligence quotient; MRI, magnetic resonance imaging; +, present; –, absent; NA, not analyzed; ACC, agenesis of corpus callosum; HCC, hypoplastic corpus callosum; ASD, atrial septum defect; AuSD, autism spectrum disorder; post., posteriorly; ∗, hg18; and ∗∗, occurrence of singular seizure. Open table in a new tab The following abbreviations are used: N, number of patients; F, female; M, male; ct, percentile; OFC, occipital-frontal circumference; IQ, intelligence quotient; MRI, magnetic resonance imaging; +, present; –, absent; NA, not analyzed; ACC, agenesis of corpus callosum; HCC, hypoplastic corpus callosum; ASD, atrial septum defect; AuSD, autism spectrum disorder; post., posteriorly; ∗, hg18; and ∗∗, occurrence of singular seizure. The phenotype associated with nonsense and frameshift mutations in ARID1B is shown in Figure 3 and summarized in Table 1. All individuals presented with moderate to severe psychomotor retardation, and most showed evidence of muscular hypotonia. In many of the patients, expressive speech was reported to be more severely affected than receptive function. Although no distinct recognizable facial gestalt could be discerned, consistent findings in most of the patients were an abnormal head shape and low-set, posteriorly rotated, and abnormally shaped ears. Even though many other minor anomalies such as downslanting palpebral fissures, a bulbous nasal tip, a thin upper lip, minor teeth anomalies, and brachydactyly or single palmar creases were observed frequently, gross malformations such as congenital heart defects, structural brain anomalies, or cleft palate were only rarely observed. The majority of patients had short stature of postnatal onset or body height within the lower normal range. With regard to these aspects, the phenotype of patients with point mutations overlaps with that observed in patients with large genomic deletions on chromosome 6q or intragenic deletions within ARID1B12Nagamani S.C. Erez A. Eng C. Ou Z. Chinault C. Workman L. Coldwell J. Stankiewicz P. Patel A. Lupski J.R. Cheung S.W. Interstitial deletion of 6q25.2-q25.3: A novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss.Eur. J. Hum. Genet. 2009; 17: 573-581Crossref PubMed Scopus (39) Google Scholar, 15Halgren C. Kjaergaard S. Bak M. Hansen C. El-Schich Z. Anderson C. Henriksen K. Hjalgrim H. Kirchhoff M. Bijlsma E. et al.Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.Clin. Genet. 2011; (Published online July 29, 2011)https://doi.org/10.1111/j.1399-0004.2011.01755.xCrossref PubMed Scopus (104) Google Scholar (such as in patient 1), further confirming that haploinsufficiency of ARID1B is indeed responsible for most of the symptoms. However, either autism spectrum disorder or autistic traits were reported in five patients with larger genomic or intragenic deletions13Nord A.S. Roeb W. Dickel D.E. Walsh T. Kusenda M. O'Connor K.L. Malhotra D. McCarthy S.E. Stray S.M. Taylor S.M. et al.STAART Psychopharmacology NetworkReduced transcript expression of genes affected by inherited and de novo CNVs in autism.Eur. J. Hum. Genet. 2011; 19: 727-731Crossref PubMed Scopus (86) Google Scholar, 15Halgren C. Kjaergaard S. Bak M. Hansen C. El-Schich Z. Anderson C. Henriksen K. Hjalgrim H. Kirchhoff M. Bijlsma E. et al.Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.Clin. Genet. 2011; (Published online July 29, 2011)https://doi.org/10.1111/j.1399-0004.2011.01755.xCrossref PubMed Scopus (104) Google Scholar but were observed in only one of our patients. Three of our five patients who underwent a cerebral magnetic resonance imaging (MRI) scan had minor unspecific anomalies such as retrocerebellar cysts, delayed myelination, and asymmetric calvaria, but none showed a hypoplastic or aplastic corpus callosum, which was considered a hallmark of the ARID1B deficiency by Halgren et al.15Halgren C. Kjaergaard S. Bak M. Hansen C. El-Schich Z. Anderson C. Henriksen K. Hjalgrim H. Kirchhoff M. Bijlsma E. et al.Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.Clin. Genet. 2011; (Published online July 29, 2011)https://doi.org/10.1111/j.1399-0004.2011.01755.xCrossref PubMed Scopus (104) Google Scholar (it was only reported in patients with larger deletions there). In addition, hearing loss was also more consistently observed in patients with larger deletions12Nagamani S.C. Erez A. Eng C. Ou Z. Chinault C. Workman L. Coldwell J. Stankiewicz P. Patel A. Lupski J.R. Cheung S.W. Interstitial deletion of 6q25.2-q25.3: A novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss.Eur. J. Hum. Genet. 2009; 17: 573-581Crossref PubMed Scopus (39) Google Scholar than in our patients with point mutations in ARID1B. These two aspects might therefore be more related to the contribution of additional genes affected by chromosomal aberrations than to haploinsufficiency of ARID1B itself. ARID1B is highly expressed in the brain and in embryonic stem cells and encodes AT-rich interactive domain-containing protein 1B, also known as BAF250b, the largest subunit of the mammalian SWI/SNF-A chromatin-remodeling complex. This complex facilitates DNA access with the use of transcription factors and the transcription machinery.16Li X.S. Trojer P. Matsumura T. Treisman J.E. Tanese N. Mammalian SWI/SNF—a subunit BAF250/ARID1 is an E3 ubiquitin ligase that targets histone H2B.Mol. Cell. Biol. 2010; 30: 1673-1688Crossref PubMed Scopus (90) Google Scholar BAF250b has a DNA-binding domain known as ARID (AT-rich interaction domain) and is thought to target the complex to specific genes.17Wang X. Nagl N.G. Wilsker D. Van Scoy M. Pacchione S. Yaciuk P. Dallas P.B. Moran E. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes.Biochem. J. 2004; 383: 319-325Crossref PubMed Scopus (142) Google Scholar BAF250b and its ortholog BAF250a (encoded by ARID1A [MIM 603024]) associate with E2F transcription factors and play important roles in cell-cycle control.18Nagl Jr., N.G. Wang X. Patsialou A. Van Scoy M. Moran E. Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control.EMBO J. 2007; 26: 752-763Crossref PubMed Scopus (191) Google Scholar Recently, it has been shown that BAF250b is also part of an E3-ubiquitin-ligase complex targeting histone H2B at lysine 120 for monoubiquitination in vitro.16Li X.S. Trojer P. Matsumura T. Treisman J.E. Tanese N. Mammalian SWI/SNF—a subunit BAF250/ARID1 is an E3 ubiquitin ligase that targets histone H2B.Mol. Cell. Biol. 2010; 30: 1673-1688Crossref PubMed Scopus (90) Google Scholar Histone H2B ubiquitination has been shown to be required for transcriptional activation in vitro19Pavri R. Zhu B. Li G. Trojer P. Mandal S. Shilatifard A. Reinberg D. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II.Cell. 2006; 125: 703-717Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar and associates with transcriptionally active genes in vivo.20Davie J.R. Murphy L.C. Inhibition of transcription selectively reduces the level of ubiquitinated histone H2B in chromatin.Biochem. Biophys. Res. Commun. 1994; 203: 344-350Crossref PubMed Scopus (40) Google Scholar, 21Minsky N. Shema E. Field Y. Schuster M. Segal E. Oren M. Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells.Nat. Cell Biol. 2008; 10: 483-488Crossref PubMed Scopus (272) Google Scholar BAF250b interacts with Elongin B/C through its B/C box and with Cullin 2 (CUL2 [MIM 603135]) through both the ARID1B and B/C boxes and assembles the complex in a manner similar to that of the well-characterized Von Hippel-Lindau (VHL) complex, which targets the hypoxia inducible factor HIF1α (MIM 603348).16Li X.S. Trojer P. Matsumura T. Treisman J.E. Tanese N. Mammalian SWI/SNF—a subunit BAF250/ARID1 is an E3 ubiquitin ligase that targets histone H2B.Mol. Cell. Biol. 2010; 30: 1673-1688Crossref PubMed Scopus (90) Google Scholar We conclude that ARID1B haploinsufficient mutations are a relatively frequent cause of moderate to severe ID, and our findings add to the growing evidence of a role of altered chromatin remodeling in the pathogenesis of ID.4Najmabadi H. Hu H. Garshasbi M. Zemojtel T. Abedini S.S. Chen W. Hosseini M. Behjati F. Haas S. Jamali P. et al.Deep sequencing reveals 50 novel genes for recessive cognitive disorders.Nature. 2011; 478: 57-63Crossref PubMed Scopus (690) Google Scholar, 22Gécz J. Shoubridge C. Corbett M. The genetic landscape of intellectual disability arising from chromosome X.Trends Genet. 2009; 25: 308-316Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 23Kraft M. Cirstea I.C. Voss A.K. Thomas T. Goehring I. Sheikh B.N. Gordon L. Scott H. Smyth G.K. Ahmadian M.R. et al.Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice.J. Clin. Invest. 2011; 121: 3479-3491Crossref PubMed Scopus (68) Google Scholar, 24Kramer J.M. van Bokhoven H. Genetic and epigenetic defects in mental retardation.Int. J. Biochem. Cell Biol. 2009; 41: 96-107Crossref PubMed Scopus (69) Google Scholar We thank the patients and their families for their cooperation. We also thank Angelika Diem, Petra Rothe, Daniela Schweizer, and Olga Zwenger for the excellent technical support. This study was supported by the German Intellectual Disability Network through a grant from the German Ministry of Education and Research to G.R., E.S., D.W., O.R., H.E., A. Rauch, and A. Reis. (01GS08160). Download .pdf (.35 MB) Help with pdf files Document S1. Description of study group, Tables S1–S4, and supplementary references The URLs for data presented herein are as follows:Berkeley Drosophila Genome Project (BDGP), http://www.fruitfly.org/Human Splicing Finder (HSF), http://www.umd.be/HSF/NetGene2 server, http://www.cbs.dtu.dk/services/NetGene2/Online Mendelian Inheritance in Man (OMIM), http://www.omim.orgPANTHER 7.0, http://www.pantherdb.org/PolyPhen-2, http://genetics.bwh.harvard.edu/pph2/SIFT, http://sift.jcvi.org/SNAP, http://www.rostlab.org/services/SNAP/SpliceView, http://zeus2.itb.cnr.it/∼webgene/wwwspliceview_ex.htmlUCSC Genome Browser, http://genome.ucsc.edu/
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