ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2015) 38 OC5.5 | DOI: 10.1530/endoabs.38.OC5.5

Investigating the genetic architecture of gland-in-situ congenital hypothyroidism by comprehensive screening of eight known causative genes

Adeline K Nicholas1, Eva Goncalves Serra2, Hakan Cangul3, Saif Al-Yaarubi4, Irfan Ullah4, Abdelhadi Habeb5, Asma Deeb6, Catherine Peters7, Mehul Dattani7,8, Savitha Shenoy9, P G Murray10, Vijith Puthi11, Soo-Mi Park12, Nisha Nathwani13, Amir Babiker14, Howard Martin15, Carl A Anderson2, Eamonn Maher15,16, V Krishna Chatterjee1 & Nadia Schoenmakers1

1University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK; 2Wellcome Trust Sanger Institute, Hinxton, UK; 3Department of Medical Genetics, Istanbul Medipol University, International School of Medicine, Istanbul, Turkey; 4Department of Paediatric Endocrinology, Sultan Qaboos University Hospital, Muscat, Oman; 5Department of Paediatrics, PMBA Hospital, Al-Madinah, Saudi Arabia; 6Department of Paediatric Endocrinology, Mafraq Hospital, Abu Dhabi, United Arab Emirates; 7Department of Endocrinology, Great Ormond Street Hospital for Children, London, UK; 8Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK; 9Department of Paediatric Endocrinology, Leicester Royal Infirmary, Leicester, UK; 10Centre for Paediatrics and Child Health, Institute of Human Development, University of Manchester, Manchester, UK; 11Department of Paediatrics, Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough, UK; 12Department of Clinical Genetics, Addenbrooke’s Hospital, Cambridge, UK; 13Department of Paediatrics, Luton & Dunstable Hospital NHS Trust, Luton, UK; 14Department of Paediatric Endocrinology, King Khalid University Hospital and King Saud University, Riyadh, Saudi Arabia; 15Cambridge NIHR Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK; 16Department of Medical Genetics, University of Cambridge, Cambridge, UK.

Background: Lower cut-offs in TSH screening have doubled the incidence of congenital hypothyroidism (CH), particularly cases with an eutopically-located Gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes, or the thyrotropin-stimulating hormone receptor (TSHR) may underlie such cases, these genes have not previously been screened comprehensively in a GIS CH cohort.

Study design: We evaluated the relative contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD and TSHR) in fifty-one CH cases with GIS from 35, ethnically diverse families, using next generation sequencing. Patient genotypes were correlated with biochemical phenotype and pathogenicity of novel mutations analysed in silico.

Results: Twenty-nine cases harboured likely, disease-causing, mutations. Twenty cases with single gene defects, most commonly involving TG (12 cases), TPO (five cases), DUOX2 (two cases) and TSHR (one case), were documented. Novel variants were identified in TG (13), TPO (6), and DUOX2 (3). Nine cases harboured pathogenic variants in two different genes: TG and TPO (1 case); SLC26A4 and TPO (two cases) and DUOX2 and TG (six cases). However, family studies in such digenic cases, showed no clear correlation between genotype and phenotype. Genetic aetiology was not ascertained in 22 patients, generally with milder biochemical CH and including some familial cases.

Conclusions: The aetiology of CH with GIS is complex, with only 57% being due to mutations in TSHR or known dyshormonogenesis-associated genes. Combinations of defects in two different genes are common, especially in consanguineous families. Severe CH is most commonly mediated by biallelic TG or TPO mutations. A high proportion (~43%) of unsolved cases suggests contribution of hitherto unknown genes or environmental factors to GIS CH.

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