Related Experiment Video
Updated: Mar 16, 2026
An Ex vivo Culture System to Study Thyroid Development
Published on: June 6, 2014
Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ
Adeline K Nicholas1, Eva G Serra1, Hakan Cangul1
1University of Cambridge Metabolic Research Laboratories (A.K.N., E.S., G.L., V.K.K.C., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Human Genetics (E.G.S., C.A.A.), The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Research Centre for Regenerative and Restorative Medicine (H.C.), Department of Medical Genetics Istanbul Medipol University, Kavacık, Istanbul, Turkey; Pediatric Endocrine Unit (S.A., I.U.), Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman; Paediatric Endocrinology Department (A.D.), Mafraq Hospital, AbuDhabi, United Arab Emirates; Pediatric Department Prince Mohamed Bin Abdulaziz Hospital (A.M.H.), Madinah, Kingdom of Saudi Arabia; Department of Paediatrics (M.A.), Madina Maternity & Children's Hospital Madina Munawara, Saudi Arabia; 8. Department of Endocrinology (C.P.), Great Ormond St Hospital for Children, London, United Kingdom; Department of Paediatrics (N.N.), Luton and Dunstable University Hospital, Luton, United Kingdom; Division of Paediatric Endocrinology (Z.A.), Dr Sami Ulus Woman Health and Children Research Hospital Ankara, Turkey; Department of Paediatric Endocrinology (H.S.), Uludağ University, School of Medicine Bursa, Turkey; Department of Paediatric Endocrinology (E.B.), Dokuz Eylül University, Faculty of Medicine Izmir, Turkey; Developmental Endocrinology Research Group (M.D.), Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London, United Kingdom; Department of Paediatrics (S.S.), Leicester Royal infirmary, Leicester United Kingdom; Centre for Paediatrics and Child Health (P.G.M.), Institute of Human Development University of Manchester, and Royal Manchester Children's Hospital, Manchester, United Kingdom; Paediatric Endocrinology Division (A.B.), College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Saudi Arabia; Department of Paediatrics (R.W., A.T.), University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; W Midlands Regional Genetics Laboratory (R.I.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham, United Kingdom; Department of Paediatric Endocrinology (R.P.), Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Department of Paediatrics (K.T.), Diana Princess of Wales Hospital, Grimsby, United Kingdom; Department of Paediatric Endocrinology (J.H.D.), University Hospital Southampton, Southampton, United Kingdom; Department of Paediatrics (V.P.), Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough, United Kingdom; Department of Clinical Genetics (S.-M.P.), Cambridge University Hospitals NHS Foundation Trust, Cambridge United Kingdom; London N W Healthcare NHS Trust (A.F.M.), Harrow, Middlesex, United Kingdom; Division of Population Medicine (J.W.G.), School of Medicine, Cardiff University, Heath Park Cardiff, UK; Department of Paediatric Endocrinology (A.A.), St George's University Hospitals NHS Foundation Trust, London, United Kingdom; Centre for Endocrinology (E.P.-G.), William Harvey Research Institute, Queen Mary University London and Children's Hospital, Barts Health NHS Trust, London, United Kingdom; Department of Medical Genetics (H.M., K.B., E.R.M.), University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
Context:
Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.
Objective:
Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.
Patients, Design, And Setting:
We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.
Results:
Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.
Conclusions:
The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
More Related Videos
05:41Author Spotlight: Integrating Ultrasound Imaging with Biochemical Markers for Thyroid Disease Diagnosis
Published on: February 9, 2024
06:50A High-Throughput Electrochemiluminescence 7-Plex Assay Simultaneously Screening for Type 1 Diabetes and Multiple Autoimmune Diseases
Published on: May 29, 2020
Related Concept Videos
01:20Synthesis and Regulation of Thyroid Hormones
Upon reaching the thyroid gland, TSH stimulates the follicular cells' active uptake of iodide ions from the blood. The ions diffuse to the apical surface of the cells and are oxidized to iodine. The...
02:46Genetic Screens
Forward genetic screens
Forward or “classical” genetic screens involve creating random mutations in an organism’s DNA using radiation, mutagens, or insertion of additional bases, which...