SOX12 and NRSN2 Are Candidate Genes for 20P13 Subtelomeric Deletions Associated with Developmental Delay

See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/256481137 SOX12 and NRSN2 Are Candidate Genes for 20p13 Subtelomeric Deletions Associated with Developmental Delay ARTICLE in AMERICAN JOURNAL OF MEDICAL GENETICS PART B NEUROPSYCHIATRIC GENETICS · DECEMBER 2013 Impact Factor: 3.42 · DOI: 10.1002/ajmg.b.32187 · Source: PubMed CITATIONS READS 2 39 13 AUTHORS, INCLUDING: Gerald Cox Ankita Patel Sanofi Aventis Group Baylor College of Medicine 84 PUBLICATIONS 3,638 CITATIONS 153 PUBLICATIONS 5,021 CITATIONS SEE PROFILE SEE PROFILE Pawel Stankiewicz Yiping Shen Baylor College of Medicine Boston Children's Hospital 197 PUBLICATIONS 7,729 CITATIONS 114 PUBLICATIONS 3,499 CITATIONS SEE PROFILE SEE PROFILE Available from: Yiping Shen Retrieved on: 25 September 2015 RESEARCH ARTICLE Neuropsychiatric Genetics SOX12 and NRSN2 Are Candidate Genes for 20p13 Subtelomeric Deletions Associated with Developmental Delay Yu An,1,2 Sami S. Amr,3,4,5 Alcy Torres,3,6 Laura Weissman,3,7 Peter Raffalli,3,6 Gerald Cox,3,8 Xiaoming Sheng,2 Va Lip,2 Weimin Bi,9 Ankita Patel,9 Pawel Stankiewicz,9 Bai-Lin Wu,1,2,3 and Yiping Shen2,3,10* 1Institutes of Biomedical Sciences, Children’s Hospital and MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China 2Department of Laboratory Medicine, Boston Children’s Hospital, Boston, Massachusetts 3Harvard Medical School, Boston, Massachusetts 4Brigham and Woman’s Hospital, Boston, Massachusetts 5Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, Massachusetts 6Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts 7Developmental Medicine Center, Boston Children’s Hospital, Massachusetts 8Genetics Program, Boston Children’s Hospital, Boston, Massachusetts 9Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 10Shanghai Children’s Medical Center, Jiaotong University School of Medicine, Shanghai, China Manuscript Received: 29 March 2013; Manuscript Accepted: 26 June 2013 20p13 telomeric/subtelomeric deletions are clinically significant but are currently under-investigated. So far only five molecularly How to Cite this Article: delineated cases have been reported in literature and no candi- An Y, Amr SS, Torres A, Weissman L, date genes have been sufficiently implicated. Here, we present six Raffalli P, Cox G, Sheng X, Lip V, Bi W, new deletion cases identified by chromosomal microarray anal- Patel A, Stankiewicz P, Wu B-L, Shen Y. ysis (CMA). We also review 32 cases combined from literature 2013. SOX12 and NRSN2 Are Candidate and databases. We found that most 20p13 deletion patients Genes for 20p13 Subtelomeric Deletions exhibit significant developmental delay. Dysmorphic features Associated With Developmental Delay. are common but a consistent pattern was not recognized. Re- duced cognitive ability was frequent. Based on pathogenic dele- Am J Med Genet Part B 162B:832–840. tions delineated in this study, we mapped the smallest overlapping region and identified two nervous system expressing genes (SOX12 and NRSN2) as candidate genes that may be involved in the developmental defects in 20p13 microdeletion. Ó 2013 Wiley Periodicals, Inc. Key words: 20p13; microdeletion; developmental delay; Yu An and Sami S. Amr contributed equally to this study. SOX12; NRSN2 No conflict of interest for all authors. Grant sponsor: Wellcome Trust; Grant sponsor: Shanghai “Eastern Scholar” program; Grant sponsor: 973 National Basic Research Program of China; Grant number: 2010CB529601. Ã INTRODUCTION Correspondence to: Yiping Shen, Ph.D., FACMG, Shanghai Children’s Medical Center, 1678 Subtelomeric deletions of 20p have been reported as pathogenic Dong Fang Road Shanghai, China 200127. imbalances in patients with developmental delay or intellectual E-mail: [email protected] disability [Ravnan et al., 2006]. Compared to the well reported Article first published online in Wiley Online Library interstitial and terminal 20p deletions involving the JAG1 gene, (wileyonlinelibrary.com): 6 September 2013 which is responsible for Alagille syndrome [Kalousek, 1976; Byrne DOI 10.1002/ajmg.b.32187 Ó 2013 Wiley Periodicals, Inc. 832 AN ET AL. 833 et al., 1986; Sauter et al., 2003], small terminal deletions of the short disorder. On physical examination, he had narrow palpebral arm of chromosome 20 (20pter) that do not span the JAG1 gene, fissures, hypoplastic ear helices, high arched palate, hypoplastic and only affect the 20p13 region, have not been well characterized fifth toenail, high arched feet, and color blindness. He had two and are currently under-reported. To date, a total of 17 patients EEGs which revealed some paroxysmal activities and very promi- have been reported in literature with subtelomeric deletions of 20p, nent hyper-synchronous bursts in sleep that lasted up to about 4 sec 12 of which were detected by fluorescence in situ hybridization but was not enough to support a clinical diagnosis of a seizure (FISH) and the range and size of these deletions were not described disorder. [Baker et al., 2002; Ravnan et al., 2006]. The remaining five 20p deletions were known to be localized to 20p13, however the clinical information of the patients carrying the 20p13 deletions was Patient 2 limited. Sebat et al. [2007] reported two patients diagnosed with Patient 2 is an 11-year-6-month-old Caucasian male who was autism and Asperger’s syndrome with de novo 20p13 deletions that diagnosed with Landau–Kleffner syndrome, autism, and global were 216 kb and 1.1 Mb in size respectively. McGill et al. [2010] developmental delay. He had delay in speech and language, social, described two patients with development delay and other features, gross and fine motor skills, and he began to walk at an age of who carried de novo 20p13 deletions that were 1.2 and 1.7 Mb in 19 months. He has a history of bouts of asthma, diarrhea, and size. More recently, Moutton et al. [2012] reported a de novo hypertonia and also has delayed closure of the anterior fontanelle, 2.08 Mb deletion in a patient with psychomotor retardation, amblyopia of the left eye, astigmatism, and late eruption of first epilepsy and low-set ears with overfolded helices. In addition, there tooth. At 2 years of age, his EEG was noted to have abnormal are a total of 27 cases currently collected in chromosomal micro- readings. At 9 years and 8 months, he presented with a short and array databases: Database of Chromosomal Imbalance and Pheno- stocky body habitus, external genitalia Tanner stage 1, and macro- type in Humans using Ensembl Resources (DECIPHER) [Firth cephaly. He had a normal neurological examination. His overall et al., 2009] and The International Standards for Cytogenomic cognitive abilities by the Woodcock–Johnson Test of Cognitive Arrays Consortium (ISCA). Here, we report six new 20p13 deletion Abilities, 3rd edition were in the low range with a standard score of cases and provide a review of clinical phenotypes observed in 20p13 85 (16th percentile). The other standard scores included a verbal deletion patients. Based on all pathogenic deletions, we mapped the comprehension at 92, concept formation at 86, and visual matching smallest overlapping region (SOR) to a 47 kb interval that contains at 86. On physical examination, distinctive features were noted only two genes. including deep-set eyes, broad nasal alae, prominent forehead with bossing, normal ears, round and flat face, short philtrum and MATERIALS AND METHODS inverted upper lip, left single palmar crease, prominent finger pads, and partial 2–3 syndactyly of both feet. Patients 1–4 were identified among 8,065 consecutive cases with clinical indications of developmental delay, intellectual disability, and/or multiple congenital anomalies referred for clinical chromo- Patient 3 somal microarray analysis (CMA) between November 2006 and Patient 3 is a 3-years-4-months-old Caucasian female diagnosed June 2012. Medical chart review was approved by the Institutional with communication disorder, not otherwise specified and a Review Board of the Boston Children’s Hospital. CMA was per- developmental coordination disorder. She had a history of both formed using Agilent 244 K comparative genomic hybridization delayed attainment of motor milestones including walking at (CGH) array as previously described [Shen et al., 2007]. Parental approximately 19 months, as well as expressive language skills. FISH was performed for Patients 1 and 2. Two cases (Patients 5 and Her most recent developmental evaluation at 2 years and 6) ascertained from Baylor College of Medical were identified using 6 months of age included administration of the Bayley Scales V8.1 array [Boone et al., 2010]. Additionally, a total of 27 cases of Infant and Toddler Development, on which she received a presented in DECIPHER (http://decipher.sanger.ac.uk) and ISCA cognitive score of 95 and a language score of 79 which are average (https://www.iscaconsortium.org/) databases were accessed on to below average compared to children of her age. She had good January 11, 2013. All genomic coordinates are in hg19. social relatedness and strong play skills and did not exhibit behaviors consistent with an autism spectrum diagnosis during administration of the Autism Diagnostic Observation Schedule. Patient 1 Her profile continued to be notable for significant expressive Patient 1 is a 16-year-9-month-old Caucasian male diagnosed with language delay including vulnerabilities in vocabulary, higher global developmental delay, pervasive

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