PMC:4574214 / 7359-12992 JSONTXT

{"project":"2_test","denotations":[{"id":"26376624-25741868-10040322","span":{"begin":5486,"end":5487},"obj":"25741868"}],"text":"Results\n\nCopy number imbalances involving ARID1Bin patients with short stature and developmental disorder\nFour thousand four hundred eleven individuals in the clinical population met our inclusion criteria (as described in methods), including 415 patients with short stature, 196 patients with tall stature and 3800 patients with normal stature. Three individuals with copy number variants encompassing ARID1B were identified among 415 patients with short stature who underwent clinical microarray analysis at Boston Children’s Hospital. The locations of the two deletions and one duplication in relation to the ARID1B gene are shown in Fig. 1.\nFig. 1 Three individuals with copy number variants encompassing ARID1B shown as tracks in the UCSC genome browser\nFigure 1\nRed tracks indicate deletion and blue track indicates duplication. The numbers associated with each track are the Z-scores of patient’s height.\nThe first patient (patient A) carries a 658 kb de novo deletion at 6q25.3 which affected only ARID1B; the second patient (patient B) carries a 6.8 Mb de novo deletion at 6q25.1-q25.3 which overlaps with the deletion in Patient 1. The height Z-score for both patients are -2.3 and -2.1 respectively. The patient with the duplication (patient C) was a 13-year-old Caucasian girl who carries a 207 Kb maternally inherited intragenic duplication at 6q25.3. Her height Z-score was -2.7. The mother’s height is below average (Z = -0.33) but not short. In addition to short stature, all three patients exhibited language impairment, facial malformation and intellectual disability. Thus all three patients exhibited syndromic short stature. Detailed clinical phenotypes and their growth curves can be found in Additional files 1 \u0026 2.\nThere were no CNVs involving ARID1B in 3800 patients with normal stature and 196 patients with tall stature in our clinical population.\n\nShort stature is a frequent feature associated with patients with ARID1B mutations\nA total of 70 patients with mutations in ARID1B (including translocation, deletion, duplication, nonsense and truncating mutations) have been described in the literature and Decipher database, many of whom have Coffin-Siris syndrome. We summarize the available clinical features of these patients in Table 1. Five patients had no height information. 22 out of the remaining 65 patients (33.8 %) had short stature. 90 % of patients have height Z-scores below -1 SD. None of the patients had height Z-scores above 0 SD. The average available Z score among patients with mutations in ARID1B is -1.86 SD. Thus, growth retardation and short stature is a common feature associated with mutations in ARID1B and Coffin-Siris syndrome.\nTable 1 Clinical features of patients with ARID1B mutationsa1–8 Halgren et al., 9–17 Hoyer et al., 18–45 Santen et al. (2013), 46-48 santen et al. (2012), 49 Michelson et al., 50–53 Nagamani et al., 54 Pirola et al., 55 Narahara et al., 56–57 Sukumar et al., 58 Hopkin et al., 59 Meng et al., 60–64 Tsurusaki et al., 65–70 from decipher database\nbThe following abbreviations are used: F female, M male, OFC occipital-frontal circumference, + present, − absent, NA not analyzed, NS not stated, ACC agenesis of corpus callosum, ASD atrial septum defect, trans translocation, del deletion, dup duplication, fx frameshift\n\nARID1B mutations in non-syndromic patients with short stature\nWe sequenced the coding regions and intron-exon boundaries of ARID1B in 48 non-syndromic short stature Chinese patients. We detected four missense variants (Fig. 2). Variants c.2351C \u003e T and c.4727C \u003e T in patients D and E respectively were inherited from their fathers and the c.2351 variant was present in a sister of normal height as well. Variants c.4346G \u003e C and c.5998G \u003e T in patients F and G were not identified in either parent. Paternity test confirmed the biological relationship between the probands and their parents (data available in Additional file 3), thus these two missense variants are de novo changes in the probands. Provocative growth hormone (GH) testing with intravenous infusion of Arginine and oral administration of clonidine was performed in the patients, following routine procedures. Patient E, F and G exhibited partial growth hormone deficiency by provocative GH testing (5-7ng/ml).Patient D had a normal growth hormone level (15.272ng/ml). None of them had intellectual disability or language impairment. Thus they are all considered to have non-syndromic short stature. Detailed clinical information of the four patients is presented in Additional file 1.\nFig. 2 ARID1B Sanger sequencing data of four patients and their parents\nThe four missense variants were all predicted to be deleterious by SIFT, PolyPhen2 and Condel (Additional file 4). They were novel variants and absent from 494 Chinese controls, the NHLBI Exome Variant Server 6500 dataset (http://evs.gs.washington.edu/EVS/) and the ExAC database (http://exac.broadinstitute.org/).\nWe detected 8 novel variants predicted to be deleterious in 494 Chinese controls. There is a significant enrichment of novel deleterious missense variants detected in short stature patients when compared to the normal Chinese controls (p = 0.016 Fisher exact test). It is unclear if the inherited variants in Patients D and E are pathogenic given the lack of segregation with short stature in the family. Partial penetrance of these two inherited variants are possible. Based on the recently published guideline for variant interpretation [9], the two de novo variants are classified as likely pathogenic and the other two variants are of uncertain significance (see Additional file 4).\n"}