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Systematic Data-Querying of Large Pediatric Biorepository Identifies Novel Ehlers-Danlos Syndrome Variant Akshatha Desai1, John J

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Systematic Data-Querying of Large Pediatric Biorepository Identifies Novel Ehlers-Danlos Syndrome Variant Akshatha Desai1, John J Desai et al. BMC Musculoskeletal Disorders (2016) 17:80 DOI 10.1186/s12891-016-0936-8 RESEARCH ARTICLE Open Access Systematic data-querying of large pediatric biorepository identifies novel Ehlers-Danlos Syndrome variant Akshatha Desai1, John J. Connolly1, Michael March1, Cuiping Hou1, Rosetta Chiavacci1, Cecilia Kim1, Gholson Lyon1, Dexter Hadley1 and Hakon Hakonarson1,2* Abstract Background: Ehlers Danlos Syndrome is a rare form of inherited connective tissue disorder, which primarily affects skin, joints, muscle, and blood cells. The current study aimed at finding the mutation that causing EDS type VII C also known as “Dermatosparaxis” in this family. Methods: Through systematic data querying of the electronic medical records (EMRs) of over 80,000 individuals, we recently identified an EDS family that indicate an autosomal dominant inheritance. The family was consented for genomic analysis of their de-identified data. After a negative screen for known mutations, we performed whole genome sequencing on the male proband, his affected father, and unaffected mother. We filtered the list of non- synonymous variants that are common between the affected individuals. Results: The analysis of non-synonymous variants lead to identifying a novel mutation in the ADAMTSL2 (p. Gly421Ser) gene in the affected individuals. Sanger sequencing confirmed the mutation. Conclusion: Our work is significant not only because it sheds new light on the pathophysiology of EDS for the affected family and the field at large, but also because it demonstrates the utility of unbiased large-scale clinical recruitment in deciphering the genetic etiology of rare mendelian diseases. With unbiased large-scale clinical recruitment we strive to sequence as many rare mendelian diseases as possible, and this work in EDS serves as a successful proof of concept to that effect. Keywords: Whole genome sequencing, Ehlers-Danlos Syndrome, Biorepository, Electronic medical records, EDS, EMR, WGS Background six major classifications: 1) Classical (Types I&II); 2) Ehlers Danlos Syndrome (EDS) describes a group of her- Hypermobile (Type III); 3) Vascular (Type IV); 4) itable disorders where collagen synthesis and fibril for- Kyphoscoliosic (Type VI); 5) Arthrochalasic (Type VIIA mation is disrupted. It affects approximately 1 in 5000 to &VIIB); and 6) Dermatosparaxic (Type VIIC) [3]. These 1 in 100,000 individuals, depending on subtype [1, 2]. can be transmitted through autosomal dominant, auto- Predominant phenotypes include articular hypermobility, somal recessive, or x-linked inheritance. Mutations in a lax joints, and fragile tissue, skin, and blood vessels. EDS number of genes involved in collagen synthesis have can be extremely debilitating, requiring preventative and been associated with different EDS subtypes, including protective measures from birth or onset of symptoms. A COL1A1, COL1A2, COL5A1, COL5A2 [2, 3], and large number of subtypes have been described, including ADAMTS2 21. All EDS Type VIIC mutations identified to date have been autosomal recessive. Here, we report on an EDS patient, with symptomology that includes * Correspondence: [email protected] 1Center for Applied Genomics, The Children’s Hospital of Philadelphia, dermatosparaxis (literally, “tearing of the skin”), which Philadelphia, 3615 Civic center Blvd, Philadelphia, PA 19104, USA is characteristic of EDS Type VIIC. 2Department of Pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA © 2016 Desai et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Desai et al. BMC Musculoskeletal Disorders (2016) 17:80 Page 2 of 10 Methods flow of de-identified phenotype information to be dir- Recruitment ectly coupled with an automated analysis pipeline, utiliz- The proband (and sister) were recruited at The Center ing high-efficiency software tools. Only encrypted/de- for Applied Genomics at The Children’s Hospital of identified data reaches the phenotype browser, where it Philadelphia under a large-scale clinical recruitment pro- can be coupled with genotyping, sequencing and other ject, A Study of the Genetic Causes of Complex Pediatric data that are available on the subjects. Of the patient Disorders, aimed at recruiting over 100,000 Children DNA samples that have consented to genetic studies, we with both common and rare medical disorders. This have >99 % availability of samples available for re- study was approved by the institutional review board of genotyping under CLIA/CAP certification or NGS, with The Children’s Hospital of Philadelphia. The proband the ~1 % loss mainly due to small amounts of blood be- and his family members consented to release of de- ing obtained from the youngest children or ineffective identified medical and genomic information for publica- DNA extraction from saliva, but saliva samples consti- tion. For the proband and sister, this was in the form of tute less than 5 % of our DNA sample sets, 95 % of parental consent. All study participants blood was drawn which are blood-derived. when they presented for a clinic visit. They consented to Diagnostic codes (e.g. 756.83) and keyword (e.g. prospective genomic analysis and analysis of electronic “Ehlers Danlos, EDS”) keyword searches identified a list medical records (EMRs). Recruitment was not targeted, of 119 patients, all of which included access to lab and and the patients came to our attention through system- diagnostic reports as described above. Patient data was atic data querying of de-identified EMR records from then re-identified through a reverse-encryption process, over 80,000 individuals recruited over the last six years. which allowed our clinical team (who have no access to Cross-referencing our biorepository with rare-disease genomic data) to conduct a complete review of the pro- codes (as defined by Online Mendelian Inheritance in band’s entire medical chart (including medical letters) Man (OMIM) code 225410 and International Statistical and family medical history. Of these 119 patients, only Classification of Diseases and Related Health Problems 9 in the case of the identified proband did we have access (ICD9) code 756.83), we identified the EDS proband to the samples of a rather complete pedigree. For this who had longitudinal EMRs that included a detailed family we had the proband being diagnosed with EDS family history and relatively extensive medical history of and father and sister having EDS like phenotype the both parents. mother and maternal half-brother were normal. EMR querying Proband’s medical history Our broad consent protocol includes extraction of DNA, The proband is currently nine years for age. He was blood/sera, access to EMRs, and the permission to per- delivered at full term through vaginal delivery. The form a wide range of genomic studies in consenting in- birth was traumatic and forceps and suctioning were dividuals. The EMR product, which captures over one used. His birth weight was 4.1 kg. He was diagnosed million clinical office visits annually, is EpicCare®, (Epic with EDS at the age of 9 months, following admission Systems, WI), and includes the reason for visit, diagnosis for joint laxity and ankle crepitus. He had slightly de- codes (ICD-9-CM format), growth measurements, medi- layed development, with ambulation at approximately cations prescribed, and referrals made. The EMR is dir- 14 months. At two years of age, he was referred to a ectly interfaced with three laboratory information neurologist with amblyopia, who noted moderate systems, including one internal and two external (Quest gross motor delay, increased shoulder girdle weakness Diagnostics, LabCorp) lab systems. All laboratory test and central hypotonia. At 2.5 years of age, delays in results are available in a structured format, mapped to his fine motor skills and speech articulation were re- Current Procedural Terminology (CPT) codes, and Lo- corded. He had difficulty chewing and had weak gical Observation Identifier Names and Codes (LOINC) mouth muscles. Difficulties in fine motor skills were as needed. All of this information is captured and moved recorded again at five years of age, and abnormal gait, into our repository in a structured format for consented poor coordination, and developmental delay were research participants. We also receive radiology reports, noted at multiple time points. At 9 years-of-age, he surgical notes, hospital discharge summaries, and Emer- was at the 99th percentile for both height (148.4 cm) gency Department summaries and dictated specialist and weight (48.3 kg) based on the Center for Disease reports. Control and Prevention (CDC) weight-for-age data. Patient data is encrypted and integrated into a custom He is normocephalic, and has a fibrous anterior fon- phenotype browser, which includes all EMR, as well as tanel. He has a slightly triangular face with slight additional survey data collected at recruitment (family mid-face flattening. His adipose tissue in his lower history/diagnoses etc.).
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