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Supplementary Appendix 1. Next generation sequencing Briefly, sequencing of exonic regions and intronic boundaries of selected genes was performed on Illumina Hiseq1500 platform for 149 gene panels, and MiSeq or NextSeq platform (Illumina, USA) for 103 gene panel, with customized library probes (SureSelect Target Enrichment Kit; Agilent Technologies ) or OS-Seq™ technology with automated target DNA capture (1). Bioinformatic data analyses included software as GATK NovoAlign (Novocraft Technologies Sdn Bhd), BCFtools and SAMtools (Sanger Institute), and Annovar for variant calling and genotyping. Filtering was performed relying on data from multiple population databases (1000 genomes database , ESP database, Exome Aggregation Consortium and ClinVar) and with commonly used “in silico” prediction tools, as previously described(2, 3). Median sequencing depth in target region was 358x and 99.8% of the nucleotides reached at least 15x coverage. All selected variants was confirmed with bi-directional Sanger sequencing. 2. Gene Panel lists tested in the study 149 genes Health in Code’(http://www.healthincode.com/servicios/genetica-medica) Pan Cardiomyopathy Panel AARS2, ABCC9, ACAD9, ACADVL, ACTA1, ACTA2, ACTC1, ACTN2, AGK, AGL, AGPAT2, ALMS1, ANK2, ANKRD1, ATPAF2, BAG3, BRAF, BSCL2, CALR3, CASQ2, CAV3, CBL, COQ2, COX15, COX6B1, CRELD1, CRYAB, CSRP3, CTF1, CTNNA3, DES, DLD, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELN, EMD, EYA4, FAH, FHL1, FHL2, FHOD3, FKRP, FKTN, FLNA, FLNC, FOXD4, GAA, GATA4, GATA6, GATAD1, GFM1, GJA1, GJA5, GLA, GLB1, GNPTAB, GUSB, HCN4, HFE, HRAS, JAG1, JPH2, JUP, KCNH2, KCNJ2, KCNJ8, KCNQ1, KLF10, KRAS, LAMA2, LAMA4, LAMP2, LDB3, LIAS, LMNA, MAP2K1, MAP2K2, MIB1, MLYCD, MRPL3, MRPS22, MTO1, MURC, MYBPC3, MYH11, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NOTCH1, NRAS, OBSL1, PDHA1, PDLIM3, PHKA1, PITX2, PKP2, PLN, PMM2, PRDM16, PRKAG2, PSEN1, PSEN2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCA, SGCB, SGCD, SHOC2, SLC22A5, SLC25A4, SMAD3, SOS1, SPRED1, SURF1, TAZ, TBX1, TBX20, TBX5, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRIM63, TSFM, TTN, TTR, TXNRD2, VCL. 103 genes Blueprint Genetics’ (http://cardiology.blueprintgenetics.com/tests/) Pan Cardiomyopathy Panel (v1.1 May 06, 2014) ABCC9, ACADVL, ACTC1, ACTN2, AGL, ANKRD1, ATP5E, BAG3, BRAF, CALR3, CASQ2, CAV3, CBL, COA5, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DMPK, DNAJC19, DNM1L, DOLK, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FHL1, FHL2, FKTN, FOXRED1, FXN, GAA, GATAD1, GLA, GLB1, GUSB, HFE, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3, LMNA, MAP2K1, MAP2K2, MRPL3, MIB1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PSEN1, PSEN2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SCO2, SDHA, SGCD, SHOC2, SLC25A3, SOS1, SPRED1, SYNE1, SYNE2, TAZ, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRIM63, TSFM, TTN, TTR, TXNRD2, VCL, XK 3. Genetic Evaluation Variant interpretation warrants several considerations: currently, ClinVar and ExAc Databases are becoming the gold standard of variant classification; they rely on multiple submitters, both clinical and research genetic Laboratories and databases, the vast majority of them located in US or Northern Europe (http://www.ncbi.nlm.nih.gov/clinvar/docs/submitter_list/). We must aknowledge that actually not all research/clinical/private genetic Laboratories are active submitters: given this fact, they still may not be representative of all population databases and their variant’s definitions are subjected to changes over times. Pathogenic / likely pathogenic mutation carriers: If identified rare variants were present in ClinVar database and classified as pathogenic or likely pathogenic, patients carrying these variants were considered pathogenic/likely pathogenic mutation carriers. Notably, familial Rare Variants absent from ExAc (http://exac.broadinstitute.org) and ClinVar, or present in ExAc with MAF < or = to 0,0004 (4) and absent from ClinVar or present in ClinVar but classified as Variant of Unknown Significance (VUS) or with conflicting interpretation , which turned to be positively co-segregating with the disease inside the family, were classified as likely pathogenic as well (e.g. FLNC truncating variants (2), PKP2 large deletion variant, OBSL1 and MYH6 variants). (4,5,6) Possibly Pathogenic rare Variants (PPrV) Carriers: Rare Variants with MAF < or = to 0,0004 in ExAc and classified as of unknown significance/conflicting interpretation in ClinVar, or absent from ClinVar , and rare variants absent from ClinVar and ExAc, were considered PPrV. Patients with sporadic DCM, or familial DCM in which no segregation study was available, carrying these PPrV as above defined (n°40 “PPrV carriers patients”), without sufficient data to rule-out pathogenicity, were considered as still eligible in Clusters. Each PPrV was carefully evaluated with the available clinical and bioinformatics evidence (5 out of 41 PPrV resulting in premature truncation -e.g. frameshift, nonsense or consensus splice site-, 28 of the remaining 36 missense variants predicted deleterious by the majority of in silico tools applied - Polyphen-2 (v2.2.2r398) HumVar; SIFT, Mutation Taster- and 8 with conflicting interpretations). A double exception to frequency cutoff criteria was made for LDB3 PPrV rs121908338 and DSC2 PPrV rs145560678 (MAF in ExAc= 0,004 and 0,001 respectively). (see Fig. 2 and Detailed PPrV information). 4. Detailed PPrV informations of “PPrV Patients” in Clusters 3 – 5 (Gene, position, Nucleotide change, Amino acid Change, eventual RS, MAF in ExAc, clinical-bionformatic comments) 4a : Cluster 3 patients OBSL1 2: 220435575 c.380C>T p.A127V - - This variant has not been found in ExAc. OBSL1 mutations have been described in 3-M Syndrome, and proposed as a candidate gene for dilated cardiomyopathy (DCM) due to its known function (cytoskeletal adaptor). However, no clinical association has been established yet. MYPN 10 :69961746 c.3654G>C p.Arg1218Ser MAF ExAc: 0.000008259 Arg1218Ser affects a highly conserved residue, up to chicken considering 11 species, which is in the region of interaction with ACTN (amino acids 945-1320), between the Ig-like domains 3 and 4 of Myopalladin. The results of the analysis with different bioinformatics predictors suggest that it is a deleterious substitution: - Polyphen-2 (v2.2.2r398) HumVar: Probably damaging, score 0.999 (score range: 0-1). - SIFT: deleterious, score 0 (score<0.05 deleterious), low confidence. - Mutation Taster: presumably deleterious, p-value=1 (range: 0-1). MYPN 10: 69970162 c.3913A>G p.M1305V MAF ExAc: 0.00003295 This variant has been submitted to CLinVar, classified as VUS. It affects Highly conserved residue, up to chicken considering 11 species, which is in the region of interaction with ACTN (amino acids 945-1320), between the Ig-like domains 3 and 4 of Myopalladin. The results of the analysis with different bioinformatics predictors suggest that it is a tolerated variant, still this information is not enough to confidently exclude a pathogenic role OBSL1 2: 220426685 c.2999G>A p.Cys1000Tyr OBSL1 2: 220435300 c.655C>G p.Gln219Glu These variants are absent in ExAc and ClinVar. They are found in double Heterozygosis. Both variants segregates with the disease inside the family. We considered the combination of these variants as likely pathogenic. DMD X: 32632565 c.1337A>G p.H446R rs72468699 MAF ExAc: 0.0003147 In silico analyses predict the substitution deleterious. Male gender patient. It has been reported in ExAc with mutation-compatible frequency. It is classified as a variant of unknown significance in ClinVar. NEXN 1: 78407863 c.1630delC p.Q544KfsX23 This truncating variant is absent in ExAc, and has been submitted to ClinVar (variation id: 180457). NEBL 10: 21101775 c.2441A>G p.Gln814Arg This variant is predicted deleterious by in silico programs PolyPhen, SIFT and MutationTaster. It has not been reported in the Exome Aggregation Consortium (ExAC) data set. DES 2:220284998 c.665G>A p.Arg222His rs367961979 MAF ExAc: 0.0003708 This variant is located at the Coil 1B region (Amino acids 152-252) of the desmin protein. It affects a highly conserved amino acid, up to Frog (considering 10 species). In silico prediction are contradictory: it is considered deleterious by SIFT and MT, and benign by PolyPhen-2 (v2.2.2r398). NEXN 1: 78383276 c.53T>C p.Val18Ala MAF ExAc: 0.000008330 This variant is absent from ClinVar. The amino acid Val18 is located in the N-terminal domain of nexilin, specifically at the first actin binding domain of this protein (residues 1-164). Val18Ala affects a moderately conserved amino acid (considering 10 species) In-silico predictors are inconclusive: -Polyphen-2 (v2.2.2r398): benign, score 0.060 (Range score: 0-1). -SIFT: Deleterious, score 0.01 (score <0.05 deleterious), low confidence. -Mutation taster: presumably disease causing, p-value: 0.668 (range: 0-1). LDB3 10: 88446830 c.349G>A p.Asp117Asn rs121908338 MAF ExAc: 0.004554 This variant has conflicting interpretation in ClinVar. Orginally reported as pathogenic, it has subsequently been reported with a rare variant’s compatible frequency. It has been reported in several families with DCM and LVNC, but segregation was not always confirmed. Functional studies are conflicting. In our case, it segregates inside the family with the disease. We can not exlude a possible role in the development of DCM. 4b: Cluster 4 patients DSC2 18: 28666574 c.907G>A p.Val303Met rs145560678 MAF ExAc: 0.001194 Reported with Conflicting
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    International Journal of Pediatric Endocrinology 2017, 2017(Suppl 1):15 DOI 10.1186/s13633-017-0054-x MEETING ABSTRACTS Open Access Abstracts from the 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society (APPES) and the 50th Annual Meeting of the Japanese Society for Pediatric Endocrinology (JSPE) Tokyo, Japan. 17-20 November 2016 Published: 28 Dec 2017 PS1 Heritable forms of primary bone fragility in children typically lead to Fat fate and disease - from science to global policy a clinical diagnosis of either osteogenesis imperfecta (OI) or juvenile Peter Gluckman osteoporosis (JO). OI is usually caused by dominant mutations affect- Office of Chief Science Advsor to the Prime Minister ing one of the two genes that code for two collagen type I, but a re- International Journal of Pediatric Endocrinology 2017, 2017(Suppl 1):PS1 cessive form of OI is present in 5-10% of individuals with a clinical diagnosis of OI. Most of the involved genes code for proteins that Attempts to deal with the obesity epidemic based solely on adult be- play a role in the processing of collagen type I protein (BMP1, havioural change have been rather disappointing. Indeed the evidence CREB3L1, CRTAP, LEPRE1, P4HB, PPIB, FKBP10, PLOD2, SERPINF1, that biological, developmental and contextual factors are operating SERPINH1, SEC24D, SPARC, from the earliest stages in development and indeed across generations TMEM38B), or interfere with osteoblast function (SP7, WNT1). Specific is compelling. The marked individual differences in the sensitivity to the phenotypes are caused by mutations in SERPINF1 (recessive OI type obesogenic environment need to be understood at both the individual VI), P4HB (Cole-Carpenter syndrome) and SEC24D (‘Cole-Carpenter and population level.
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.