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Novel Features of 3Q29 Deletion Syndrome

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Novel Features of 3Q29 Deletion Syndrome Novel features of 3q29 deletion syndrome: Results from the 3q29 registry MR Glassford, Emory University JA Rosenfeld, Baylor College of Medicine AA Freedman, Emory University Michael Zwick, Emory University Jennifer Mulle, Emory University Journal Title: American Journal of Medical Genetics Part A Volume: Volume 170, Number 4 Publisher: Wiley: 12 months | 2014-04-01, Pages 999-1006 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1002/ajmg.a.37537 Permanent URL: https://pid.emory.edu/ark:/25593/rnhtx Final published version: http://dx.doi.org/10.1002/ajmg.a.37537 Copyright information: © 2016 Wiley Periodicals, Inc. This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/). Accessed September 28, 2021 11:37 PM EDT RESEARCH ARTICLE Novel Features of 3q29 Deletion Syndrome: Results From the 3q29 Registry Megan R. Glassford,1 Jill A. Rosenfeld,2 Alexa A. Freedman,3 Michael E. Zwick,1,4 Unique Rare Chromosome Disorder Support Group,5 and Jennifer G. Mulle1,3* 1Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 3Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 4Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 5Unique Rare Chromosome Disorder Support Group, Surrey, United Kingdom Manuscript Received: 25 August 2015; Manuscript Accepted: 9 December 2015 3q29 deletionsyndrome iscausedbya recurrent,typicallyde novo heterozygous 1.6 Mb deletion, but because incidence of the How to Cite this Article: deletion is rare (1 in 30,000 births) the phenotype is not well Glassford MR, Rosenfeld JA, Freedman AA, described. To characterize the range of phenotypic manifesta- Zwick ME, Unique Rare Chromosome tions associated with 3q29 deletion syndrome, we have developed Disorder Support Group, Mulle JG. 2016. an online registry (3q29deletion.org) for ascertainment of study Novel features of 3q29 deletion syndrome: subjects and phenotypic data collection via Internet-based survey Results from the 3q29 registry. instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the Am J Med Genet Part A 9999A:999–1006. largest cohort of 3q29 deletion carriers ever assembled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anx- there are rare reports of inheritance [Digilio et al., 2009]. The iety disorder, panic attacks, depression, bipolar disorder, and typical recurrent, interstitial deletion is 1.6 Mb in size and schizophrenia. Other novel findings include a high prevalence contains 22 protein-coding genes and three antisense transcripts. (64%) of feeding problems in infancy and reduced weight at birth In addition to intellectual disability [Willatt et al., 2005; Ballif for 3q29 deletion carriers (average reduction 13.9 oz (394 g), et al., 2008], the deletion is associated with bipolar disorder adjusted for gestational age and sex, P ¼ 6.5e-07). We further [Quintero-Rivera et al., 2010; Green et al., 2016] and schizo- report on the frequency of heart defects, autism, recurrent ear phrenia [Mulle et al., 2010; Mulle, 2015]. The syndrome was first infections, gastrointestinal phenotypes, and dental phenotypes, described in 2005 in six patients with a recurrent deletion [Willatt among others. We also report on the expected timing of delayed et al., 2005], presenting with mild to moderate intellectual developmental milestones. This is the most comprehensive de- disability that was not apparent until after the first year of life scription of the 3q29 deletion phenotype to date. These results are [Willatt et al., 2005]. Facial dysmorphology was subtle and clinically actionable toward improving patient care for 3q29 included a long and narrow face, short philtrum, and high nasal deletion carriers, and can guide the expectations of physicians bridge [Willatt et al., 2005]. Additional features observed in some and parents. These data also demonstrate the value of patient- reported outcomes to reveal the full phenotypic spectrum of rare This is an open access article under the terms of the Creative Commons genomic disorders. Ó 2016 The Authors. American Journal of Medical Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly Genetics Part A Published by Wiley Periodicals, Inc. cited and is not used for commercial purposes. Grant sponsor: NIH; Grant numbers: MH100917, GM097331; Key words: 3q29 deletion; 3q29 microdeletion; autism spectrum Grant sponsor: Emory University Treasure Your Exceptions Fund. disorder; schizophrenia; copy number variation; developmental ÃCorrespondence to: delay; genomic disorders; patient-reported outcomes Jennifer G. Mulle, M.H.S., Ph.D., Department of Epidemiology, Rollins School of Public Health, Emory University, Mailstop 1518-022-3BB, CNR 4053, 1518 Clifton Road, Atlanta, GA 30322. INTRODUCTION E-mail: [email protected] Article first published online in Wiley Online Library The incidence for 3q29 deletion is estimated to be one in 30–40,000 (wileyonlinelibrary.com): 6 January 2016 births [Stefansson et al., 2014] and is frequently de novo, though DOI 10.1002/ajmg.a.37537 Ó 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. 999 1000 AMERICAN JOURNAL OF MEDICAL GENETICS PART A but not all of these patients included chest-wall deformity, long MATERIALS AND METHODS and tapering fingers, microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear An internet-based registry was created (Patient Crossroads, La infections, and abnormal pigmentation. Notably, two of these six Jolla, CA) to ascertain individuals with 3q29 deletion syndrome. patients had a diagnosis of autism and a third was described as Recruitment of study subjects, informed consent, assent, HIPPA having autistic features [Willatt et al., 2005]. The phenotypic authorization, and data collection are all enabled by the website. description was expanded in 2008; 15 patients were characterized Emory University’s Institutional Review Board (IRB00064133) [Ballif et al., 2008]. Phenotypes included large, posteriorly ro- approved this study. Emails bearing information about the registry tated ears, speech and developmental delay, high-arched palate, were sent to health care providers, medical geneticists, genetic widely-spaced teeth, macrocephaly, patent ductus arteriosus, counselors, and support organizations. The registry is also adver- clinodactly, and camptodactly [Ballif et al., 2008]. Four of the tised via an internet campaign (Google AdWords) wherein a series 15 patients (27%) had autism (ASD) or autistic features. of specific keywords were chosen to target the website. Individuals Case reports have provided additional insights into the hetero- who register and complete informed consent have a personal geneity of 3q29 deletion syndrome. Cobb et al. described a seven- profile page, where they can complete data collection instruments. year-old boy with a 1.3Mb 3q29 deletion with low average to Answers may be submitted by an individual with 3q29 deletion average IQ, some dysmorphic features of 3q29 deletion syndrome, syndrome or a family member (usually a parent or guardian) if the and a diagnosis of ASD [Cobb et al., 2010]. A case report on four 3q29 deletion patient is underage or not capable of submitting individuals found “withdrawal, anxiety/depression, thought prob- answers. At registration, information is collected about the partic- lems,” problems interacting in social environments, and aggres- ipant (the person with the condition), including gender, birthdate, siveness to be a commonality for all four patients [Citta et al., 2013]. race, and ethnicity. Contact information is obtained for the par- One of the four patients was described as having a history of ticipant and the informant. A medical questionnaire was developed psychotic outbursts and another patient exhibited symptoms by selecting questions from a larger “question library” containing consistent with a diagnosis of pervasive developmental disorder, all questions from existing registries that are managed by Patient not otherwise specified (PDD-NOS). Another case report de- Crossroads. Seven health-related domains were intentionally pri- scribed two cases: a 10-year-old female and a 15-year-old male oritized for data collection based on medical issues previously [Quintero-Rivera et al., 2010]. The female patient became noted in 3q29 individuals [Ballif et al., 2008; Cox and Butler, 2015]. completely nonverbal between five and seven years of age and All domains could be assessed with existing questions; no new or was diagnosed with ASD at the age of five. She experienced auditory custom questions were developed. The website and questionnaire hallucinations, exhibited intense episodes of anger and violence were beta-tested for functionality by research staff. No pilot study towards others, and was diagnosed with bipolar disorder with was conducted. Data presented here are based on 20 questions from psychotic features by the age of 10. The male patient was diagnosed the medical questionnaire related to 7 domains: Birth History, with ASD at the age of six, and was later
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