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Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.
Marees AT, Hammerschlag AR, Bastarache L, de Kluiver H, Vorspan F, van den Brink W, Smit DJ, Denys D, Gamazon ER, Li-Gao R, Breetvelt EJ, de Groot MCH, Galesloot TE, Vermeulen SH, Poppelaars JL, Souverein PC, Keeman R, de Mutsert R, Noordam R, Rosendaal FR, Stringa N, Mook-Kanamori DO, Vaartjes I, Kiemeney LA, den Heijer M, van Schoor NM, Klungel OH, Maitland-Van der Zee AH, Schmidt MK, Polderman TJC, van der Leij AR, Posthuma D, Derks EM
(2018) Drug Alcohol Depend 188: 94-101
MeSH Terms: Alcohol Drinking, Alcoholism, Cohort Studies, Exons, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Risk Factors, Tobacco Use, Tobacco Use Disorder
Show Abstract · Added May 26, 2018
BACKGROUND - Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.
METHODS - We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.
RESULTS - The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10) and rs8034191 (p = 6.31 × 10) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.
DISCUSSION - Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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15 MeSH Terms
A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.
Sullivan LS, Bowne SJ, Koboldt DC, Cadena EL, Heckenlively JR, Branham KE, Wheaton DH, Jones KD, Ruiz RS, Pennesi ME, Yang P, Davis-Boozer D, Northrup H, Gurevich VV, Chen R, Xu M, Li Y, Birch DG, Daiger SP
(2017) Invest Ophthalmol Vis Sci 58: 2774-2784
MeSH Terms: Adult, Aged, Arrestin, DNA Mutational Analysis, Exons, Female, Genes, Dominant, High-Throughput Nucleotide Sequencing, Hispanic Americans, Humans, Male, Middle Aged, Mutation, Missense, Pedigree, Retina, Retinitis Pigmentosa, Southwestern United States
Show Abstract · Added March 14, 2018
Purpose - To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.
Methods - Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.
Results - Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.
Conclusions - This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.
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17 MeSH Terms
Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy.
Kasper S, Reis H, Ziegler S, Nothdurft S, Mueller A, Goetz M, Wiesweg M, Phasue J, Ting S, Wieczorek S, Even A, Worm K, Pogorzelski M, Breitenbuecher S, Meiler J, Paul A, Trarbach T, Schmid KW, Breitenbuecher F, Schuler M
(2017) Oncotarget 8: 45898-45917
MeSH Terms: Antineoplastic Agents, Immunological, Apoptosis, Biomarkers, Cell Line, Tumor, Colorectal Neoplasms, Drug Resistance, Neoplasm, ErbB Receptors, Exons, Genes, ras, Humans, Mitogen-Activated Protein Kinases, Mutation, Odds Ratio, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Signal Transduction
Show Abstract · Added March 17, 2018
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK- or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1- and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in a cohort of mCRC patients receiving cetuximab-based therapy. Dual pharmacologic inhibition of PI3K and MEK successfully sensitized primary resistant CRC models to anti-EGFR therapy. In conclusion, combined targeting of MAPK and PI3K/AKT signaling, but not single pathways, may be required to enhance the efficacy of anti-EGFR antibody therapy in patients with RAS-mutated CRC as well as in RAS wild type tumors with clinical resistance.
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EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.
Konduri K, Gallant JN, Chae YK, Giles FJ, Gitlitz BJ, Gowen K, Ichihara E, Owonikoko TK, Peddareddigari V, Ramalingam SS, Reddy SK, Eaby-Sandy B, Vavalà T, Whiteley A, Chen H, Yan Y, Sheehan JH, Meiler J, Morosini D, Ross JS, Stephens PJ, Miller VA, Ali SM, Lovly CM
(2016) Cancer Discov 6: 601-11
MeSH Terms: Adult, Antineoplastic Agents, Biomarkers, Cell Line, Tumor, Combined Modality Therapy, ErbB Receptors, Exons, Female, Genetic Loci, High-Throughput Nucleotide Sequencing, Humans, Introns, Lung Neoplasms, Magnetic Resonance Imaging, Male, Middle Aged, Models, Molecular, Molecular Targeted Therapy, Neoplasm Metastasis, Oncogene Proteins, Fusion, Protein Conformation, Protein Kinase Inhibitors, Rad51 Recombinase, Young Adult
Show Abstract · Added April 8, 2017
UNLABELLED - Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.
SIGNIFICANCE - We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.
©2016 American Association for Cancer Research.
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Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes.
Williams JM, Bonami RH, Hulbert C, Thomas JW
(2015) J Immunol 195: 853-64
MeSH Terms: Animals, Autoantibodies, Autoimmunity, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin G, Immunoglobulin M, Insulin, Insulin Antibodies, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, VDJ Exons
Show Abstract · Added December 4, 2015
Autoreactive B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoantibodies that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH-125 site directed to the native IgH locus (VH125(SD)). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent immunization of VH125(SD) mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, costimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Furthermore, VH125(SD) mice produce both IgM and IgG2a anti-insulin Abs following immunization with insulin conjugated to type 1 T cell-independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM(+) and IgM(-) GL7(+)Fas(+) germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igκ genes in VH125(SD) mice immunized with insulin-BRT reveals that anti-insulin Vκ from the preimmune repertoire is selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in T cell-dependent immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet underappreciated role in driving loss of tolerance and promoting autoimmune disease.
Copyright © 2015 by The American Association of Immunologists, Inc.
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17 MeSH Terms
A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia.
Carroll C, Hunley TE, Guo Y, Cortez D
(2015) Am J Med Genet A 167A: 2260-4
MeSH Terms: Arteriosclerosis, Child, DNA Helicases, DNA Replication, Exons, Female, Gene Expression, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Introns, Lymphocytes, Mutation, Nephrotic Syndrome, Osteochondrodysplasias, Pedigree, Pulmonary Embolism, RNA Splice Sites
Show Abstract · Added February 4, 2016
Schimke Immunoosseous Dysplasia (SIOD) is a rare, autosomal recessive disorder of childhood characterized by spondyloepiphyseal dysplasia, focal segmental glomerulosclerosis and renal failure, T-cell immunodeficiency, and cancer in certain instances. Approximately half of patients with SIOD are reported to have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA translocase that localizes to sites of DNA replication and repairs damaged replication forks. We present a novel mutation (NM_014140.3:c.2070+2insT) that results in defective SMARCAL1 mRNA splicing in a child with SIOD. This mutation, within the donor site of intron 12, results in the skipping of exon 12, which encodes part of a critical hinge region connecting the two lobes of the ATPase domain. This mutation was not recognized as deleterious by diagnostic SMARCAL1 sequencing, but discovered through next generation sequencing and found to result in absent SMARCAL1 expression in patient-derived lymphoblasts. The splicing defect caused by this mutation supports the concept of exon definition. Furthermore, it illustrates the need to broaden the search for SMARCAL1 mutations in patients with SIOD lacking coding sequence variants.
© 2015 Wiley Periodicals, Inc.
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18 MeSH Terms
TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.
Diogo D, Bastarache L, Liao KP, Graham RR, Fulton RS, Greenberg JD, Eyre S, Bowes J, Cui J, Lee A, Pappas DA, Kremer JM, Barton A, Coenen MJ, Franke B, Kiemeney LA, Mariette X, Richard-Miceli C, Canhão H, Fonseca JE, de Vries N, Tak PP, Crusius JB, Nurmohamed MT, Kurreeman F, Mikuls TR, Okada Y, Stahl EA, Larson DE, Deluca TL, O'Laughlin M, Fronick CC, Fulton LL, Kosoy R, Ransom M, Bhangale TR, Ortmann W, Cagan A, Gainer V, Karlson EW, Kohane I, Murphy SN, Martin J, Zhernakova A, Klareskog L, Padyukov L, Worthington J, Mardis ER, Seldin MF, Gregersen PK, Behrens T, Raychaudhuri S, Denny JC, Plenge RM
(2015) PLoS One 10: e0122271
MeSH Terms: Arthritis, Rheumatoid, Autoimmunity, Cell Adhesion Molecules, Electronic Health Records, Exons, Genetic Loci, Genetic Pleiotropy, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, TYK2 Kinase
Show Abstract · Added March 14, 2018
Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P(omnibus) = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
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11 MeSH Terms
PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers.
Castaneda CA, Lopez-Ilasaca M, Pinto JA, Chirinos-Arias M, Doimi F, Neciosup SP, Rojas KI, Vidaurre T, Balko JM, Arteaga CL, Gomez HL
(2014) Hematol Oncol Stem Cell Ther 7: 142-8
MeSH Terms: Biomarkers, Tumor, Breast Neoplasms, Class I Phosphatidylinositol 3-Kinases, Cohort Studies, Exons, Female, Gene Amplification, Humans, Middle Aged, Mutation, Neoadjuvant Therapy, Peru, Phosphatidylinositol 3-Kinases, Receptor, ErbB-2, Triple Negative Breast Neoplasms
Show Abstract · Added April 6, 2017
PURPOSE - To determine the frequency of PIK3CA mutations in a Peruvian cohort with HER2-amplified and triple negative breast cancers (TNBC).
METHODS - We analyzed two cohorts of 134 primary non-metastatic breast cancer patients from Peru. Cohorts consisted of 51 hormone receptors (+)/HER2-amplified breast tumor patients surgically resected as first treatment included in the ALTTO trial (ALTTO cohort) and 81 TNBC patients with residual disease after neoadjuvant treatment (neoadjuvant cohort). Genomic DNA was extracted from paraffin-embedded tumor samples. Samples from the ALTTO and neoadjuvant cohorts were taken at biopsies and from residual tumors, respectively. PIK3CA mutations were detected by sequencing DNA fragments obtained by PCR amplification of exons and their flanking introns. All of the detected PIK3CA mutations were confirmed in a second independent run of sample testing.
RESULTS - PIK3CA mutations were present in 21/134 cases (15.7%). Mutations in exon 9 and 20 were present in 10/134 (7.5%) and 11/134 (8.2%), respectively. No cases had mutations in both exons. Mutations in exon 9 consisted of E545A (seven cases), E545K (two cases) and E545Q (one case); while in exon 20, mutations consisted of H1047R (10 cases) and H1047L (one case). Compared to TNBC patients, HER2-amplified patients were more likely to have PIK3CA mutated (23% vs 9.6%; P=0.034). There were no associations between mutational status of PIK3CA with estrogen receptor status (P=0.731), progesterone receptor status (P=0.921), age (P=0.646), nodal status (P=0.240) or histological grade (P=1.00). No significant associations were found between PIK3CA mutational status and clinicopathological features.
CONCLUSIONS - We found a similar frequency of PIK3CA mutations to that reported in other series. Although we did not include HR+/HER2 patients, those with HER2-amplified tumors were more likely to present PIK3CA mutations compared to patients with triple negative tumors.
Copyright © 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.
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15 MeSH Terms
Global deletion of Ankrd1 results in a wound-healing phenotype associated with dermal fibroblast dysfunction.
Samaras SE, Almodóvar-García K, Wu N, Yu F, Davidson JM
(2015) Am J Pathol 185: 96-109
MeSH Terms: Adenoviridae, Animals, Cell Movement, Collagen, Crosses, Genetic, Exons, Female, Fibroblasts, Gels, Gene Deletion, Gene Expression Profiling, Genotype, Green Fluorescent Proteins, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle Proteins, Necrosis, Nuclear Proteins, Organ Size, Phenotype, Promoter Regions, Genetic, RNA, Recombination, Genetic, Repressor Proteins, Skin, Wound Healing
Show Abstract · Added January 20, 2015
The expression of ankyrin repeat domain protein 1 (Ankrd1), a transcriptional cofactor and sarcomeric component, is strongly elevated by wounding and tissue injury. We developed a conditional Ankrd1(fl/fl) mouse, performed global deletion with Sox2-cre, and assessed the role of this protein in cutaneous wound healing. Although global deletion of Ankrd1 did not affect mouse viability or development, Ankrd1(-/-) mice had at least two significant wound-healing phenotypes: extensive necrosis of ischemic skin flaps, which was reversed by adenoviral expression of ANKRD1, and delayed excisional wound closure, which was characterized by decreased contraction and reduced granulation tissue thickness. Skin fibroblasts isolated from Ankrd1(-/-) mice did not spread or migrate on collagen- or fibronectin-coated surfaces as efficiently as fibroblasts isolated from Ankrd1(fl/fl) mice. More important, Ankrd1(-/-) fibroblasts failed to contract three-dimensional floating collagen gels. Reconstitution of ANKRD1 by adenoviral infection stimulated both collagen gel contraction and actin fiber organization. These in vitro data were consistent with in vivo wound closure studies, and suggest that ANKRD1 is important for the proper interaction of fibroblasts with a compliant collagenous matrix both in vitro and in vivo.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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30 MeSH Terms
TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib).
Molinaro A, Tiosano D, Takatani R, Chrysis D, Russell W, Koscielniak N, Kottler ML, Agretti P, De Marco G, Ahtiainen P, Christov M, Mäkitie O, Tonacchera M, Jüppner H
(2015) J Bone Miner Res 30: 906-12
MeSH Terms: Adult, Child, Preschool, Chromosomes, Human, Pair 20, Epigenesis, Genetic, Exons, Female, Humans, Infant, Infant, Newborn, Male, Pseudohypoparathyroidism, Syntaxin 16, Thyrotropin, Young Adult
Show Abstract · Added May 5, 2016
Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications.
© 2014 American Society for Bone and Mineral Research.
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14 MeSH Terms