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Highly Sensitive Diagnosis of 43 Monogenic Forms

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Highly Sensitive Diagnosis of 43 Monogenic Forms 460 Diabetes Care Volume 37, February 2014 Amelie´ Bonnefond,1,2,3,4 Julien Philippe,1,2,3 Highly Sensitive Diagnosis of 43 Emmanuelle Durand,1,2,3 Jean Muller,5,6 Sadia Saeed,7 Muhammad Arslan,8 Monogenic Forms of Diabetes or Rosa Mart´ınez,9 Franck De Graeve,1,2,3 Veronique´ Dhennin,1,2,3 Obesity Through One-Step PCR- Iandry Rabearivelo,1,2,3 Michel Polak,10,11 Hel´ ene` Cave,´ 12 Luis Castano,~ 9 Based Enrichment in Combination Martine Vaxillaire,1,2,3 Jean-Louis Mandel,5,6,13 Olivier Sand,1,2,3 With Next-Generation Sequencing and Philippe Froguel1,2,3,4,7 1European Genomic Institute for Diabetes, Lille, France 2CNRS UMR8199, Pasteur Institute of Lille, Lille, France 3Lille 2 University, Lille, France OBJECTIVE 4Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar Accurate etiological diagnosis of monogenic forms of diabetes and obesity is 5Institut de Gen´ etique´ et de Biologie Moleculaire´ useful as it can lead to marked improvements in patient care and genetic coun- et Cellulaire, CNRS UMR7104, INSERM U964, seling. Currently, molecular diagnosis based on Sanger sequencing is restricted to Universite´ de Strasbourg, Illkirch, France 6 ˆ only a few genes, as this technology is expensive, time-consuming, and labor- Laboratoire de Diagnostic Gen´ etique,´ Hopitaux Universitaires de Strasbourg, Strasbourg, France intensive. High-throughput next-generation sequencing (NGS) provides an op- 7Department of Genomics of Common Disease, portunity to develop innovative cost-efficient methods for sensitive diabetes and Hammersmith Hospital, Imperial College obesity multigene screening. London, London, U.K. 8Department of Biological Sciences, Forman RESEARCH DESIGN AND METHODS Christian College, Lahore, Pakistan 9Cruces University Hospital, Universidad del Pa´ıs We assessed a new method based on PCR enrichment in microdroplets (Rain- Vasco/Euskal Herriko Unibertsitatea, Spanish Dance Technologies) and NGS using the Illumina HiSeq2000 for the molecular Biomedical Research Centre in Diabetes and EMERGING TECHNOLOGIES AND THERAPEUTICS diagnosis of 43 forms of monogenic diabetes or obesity. Forty patients carrying a Associated Metabolic Disorders, Barakaldo, known causal mutation for those subtypes according to diagnostic laboratories Spain 10INSERM U845, Universite´ Paris Descartes, were blindly reanalyzed. Sorbonne Paris Cite,´ Paris, France 11Department of Paediatric Endocrinology, RESULTS Necker Enfants-Malades Hospital, Assistance Except for one variant, we reidentified all causal mutations in each patient as- Publique-Hopitauxˆ de Paris, Paris, France 12Department of Genetics, Robert-Debre´ sociated with an almost-perfect sequencing of the targets (mean of 98.6%). We ˆ fi Hospital, Assistance Publique-Hopitaux de Paris, failed to call one highly complex indel, although we identi ed a dramatic drop of Paris, France coverage at this locus. In three patients, we detected other mutations with a 13Chaire de Gen´ etique´ Humaine, College` de putatively deleterious effect in addition to those reported by the genetic diag- France, Illkirch, France nostic laboratories. Corresponding author: Philippe Froguel, [email protected]. CONCLUSIONS Received 22 March 2013 and accepted 10 Our NGS approach provides an efficient means of highly sensitive screening for September 2013. mutations in genes associated with monogenic forms of diabetes and obesity. As This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ cost and time to deliver results have been key barriers to uncovering a molecular suppl/doi:10.2337/dc13-0698/-/DC1. cause in the many undiagnosed cases likely to exist, the present methodology A.B. and J.P. contributed equally to this work. should be considered in patients displaying features of monogenic diabetes or © 2014 by the American Diabetes Association. obesity. See http://creativecommons.org/licenses/by- Diabetes Care 2014;37:460–467 | DOI: 10.2337/dc13-0698 nc-nd/3.0/ for details. care.diabetesjournals.org Bonnefond and Associates 461 Type 2 diabetes and obesity are complex cost-efficient, and rapid method to Primer Library Design disorders that are associated with identify causal mutations in patients We selected all susceptibility genes for several factors of genetic, epigenetic, with monogenic disorders (10). monogenic forms of diabetes or obesity, and environmental origins (1,2). Familial However, this technology is not which were known at the time of the aggregation of both type 2 diabetes and currently perfect for clinical molecular design (n = 43; Table 1 and obesity demonstrates a high heritability diagnosis, as it leads to marked gaps of Supplementary Table 1). All exons, (between 40 and 70%), which can make sequence (.5% of the target regions, including at least 40 base pairs (bp) of it difficult to select cases more likely to even with high mean depth of the flanking intron of each exon, and have a monogenic cause (1,3). However, sequencing coverage) (10,11), which is 1,000 bp upstream of exon 1 and deleterious coding gene mutations have problematic when the investigators are downstream of the last exon were been shown to cause almost totally looking for only one causal mutation. targeted. The primer library was penetrant severe forms of diabetes and In the current study, we aimed to designed using proprietary pipeline obesity, including neonatal diabetes assess a new method based on PCR developed by RainDance Technologies fl mellitus (NDM), maturity-onset enrichment in microfluidic droplets and (Lexington, MA). Brie y, primer diabetes of the young (MODY) and next-generation sequencing (NGS) for selection was based upon standard PCR several related syndromes like Bardet- the molecular diagnosis of 43 subtypes criteria, namely guanine-cytosine Biedl syndrome (BBS), Alstrom¨ of monogenic diabetes or obesity. content between 25 and 80%, amplicon syndrome (ALMS), Wolcott-Rallison, or A total of 40 patients carrying a known length between 200 and 600 bp, melting 8 Wolfram syndrome (4,5). All of these causal mutation for those subtypes temperature between 56 and 60 C, and monogenic forms of diabetes and according to genetic diagnostic primer length between 15 and 33 bp. obesity tend to occur at younger ages laboratories were blindly included in the Suitable primers were then screened and often exhibit other clinical features study. against the dbSNP131 database to (4,5). remove all primers that hybridized to polymorphism containing targeted In this context, an accurate molecular RESEARCH DESIGN AND METHODS sequences. The 542 targeted exons diagnosis of these extreme and often Patient Selection were covered by 970 primer pairs familial forms of diabetes and obesity is We selected a total of 40 patients (targeting a total of 336 kb of sequence) crucial for an optimal care of the presenting with a monogenic form of that were encapsulated into patients and genetic counseling for their diabetes (n = 19) or obesity (n = 21) who microfluidic droplets via RainDance families. The most striking example is were carriers of a known causal Technologies (Table 1). seen for the NDM patients carrying a mutation according to diagnostic heterozygous point mutation in the laboratories: 9 NDM patients, primarily Microdroplet-Based PCR Enrichment ABCC8 or KCNJ11 gene, encoding the assessed by the Department of Genetics The 40 DNA samples (3 mg) were two subunits (SUR1 and KIR6.2, in Robert-Debre´ Hospital (Assistance fragmented to 2–4 kb by sonication ˆ respectively) of the pancreatic b-cell– Publique-Hopitaux de Paris, Paris, (Bioruptor NGS; Diagenode, Liege,` + expressed ATP-dependent K channels. France); 10 MODY patients, primarily Belgium) and purified using the Indeed, these patients can be optimally assessed by the Cruces University MinElute system (Qiagen, Valencia, CA). treated by oral sulfonylurea drugs Hospital- Centro de Investigacion´ The quality of both fragmentation and instead of lifelong insulin therapy, Biomedica´ en Red de Diabetes y purification was assessed using the 2100 leading to remarkable improvements in Enfermedades Metabolicas´ Asociada Bioanalyzer (Agilent Technologies, glucose control and quality of life (6–8). (n = 5; Barakaldo, Spain) and the CNRS Santa Clara, CA). Subsequently, the Furthermore, a recent study UMR8199 unit (n = 5; Lille, France); 12 RainDance primer library was merged demonstrated that personalized genetic patients with an early-onset severe with each sheared genomic DNA sample medicine applied to patients with NDM, obesity, primarily assessed by the on the RDT1000 (RainDance which is currently based on standard Department of Genomics of Common Technologies), according to the Sanger sequencing of KCNJ11 and Disease in Imperial College of London manufacturer’s protocol. The resulting ABCC8 that is performed by clinical (n = 6; London, U.K.) and the CNRS emulsion, containing ;1million diagnostic laboratories (at a cost of UMR8199 unit (n = 6; Lille, France); and potential PCR reactions, was $2,815 in the U.S. [9]), leads to high 9 BBS patients, primarily assessed by the subsequently amplified by PCR on the financial benefits (9). However, as Genetic Diagnostic Laboratory in the Mastercycler Pro S (Eppendorf, ˆ KCNJ11 and ABCC8 encode a total of 40 Hopitaux Universitaires de Strasbourg Hamburg, Germany). The addition of coding exons, this genetic testing is (Strasbourg, France). Destabilizer reagent (RainDance obviously time-consuming, labor- The study protocol was approved by all Technologies) resulted in the intensive, and restricted to two genes local
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