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2. An approach to quantifying abnormalities in energy expenditure and lean mass in metabolic disease

Author

Watson, L.P.E., Raymond-Barker, P., Moran, C., Schoenmakers, N., Mitchell, C., Bluck, L., Chatterjee, V.K., Savage, D.B., and Murgatroyd, P.R.

Subjects
Body composition -- Measurement, Bioenergetics -- Measurement, Energy metabolism -- Measurement, Metabolic diseases -- Physiological aspects, Food/cooking/nutrition, Health
Abstract

BACKGROUND/OBJECTIVES: The objective of this study was to develop approaches to expressing resting energy expenditure (REE) and lean body mass (LM) phenotypes of metabolic disorders in terms of Z- scores relative to their predicted healthy values. SUBJECTS/METHODS: Body composition and REE were measured in 135 healthy participants. Prediction equations for LM and REE were obtained from linear regression and the range of normality by the standard deviation of residuals. Application is demonstrated in patients from three metabolic disorder groups (lipodystrophy, n = 7; thyrotoxicosis, n = 16; and resistance to thyroid hormone (RTH), n = 46) in which altered REE and/or LM were characterised by departure from the predicted healthy values, expressed as a Z-score. RESULTS: REE (kJ/min) = -0.010 x age (years) + 0.016 x FM (kg) + 0.054 x fat- free mass (kg) + 1.736 ([R.sup.2] = 0.732, RSD = 0.36kJ/min). LM (kg) = 5.30 x bone mineral content (kg) + 10.66 x [height.sup.2] (m) + 6.40 (male). LM (kg) = 0.20 x fat (kg) + 14.08 x [height.sup.2] (m) - 2.93 (female). (male [R.sup.2] = 0.55, RSD = 3.90 kg; female [R.sup.2] = 0.59, RSD = 3.85 kg). We found average Z-scores for REE and LM of 1.77 kJ/min and -0.17 kg in the RTH group, 5.82 kJ/min and -1.23 kg in the thyrotoxic group and 2.97 kJ/min and 4.20 kg in the LD group. CONCLUSION: This approach enables comparison of data from individuals with metabolic disorders with those of healthy individuals, describing their departure from the healthy mean by a Z-score. European Journal of Clinical Nutrition (2014) 68, 234-240; doi: 10.1038/ejcn.2013.237; published online 27 November 2013 Keywords: resting energy expenditure; lean mass; body composition; Z-score; metabolic disease, INTRODUCTION Many metabolic disorders such as thyroid disease or lipodystrophy (LD) are associated with changes in body composition, energy expenditure or both. (1,2) In describing the phenotypes of such conditions, [...]

Published
2014
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7. The IGSF1 Deficiency Syndrome: Characteristics of Male and Female Patients

Author

Joustra, S. D., Schoenmakers, N., Persani, L., Campi, I., Bonomi, M., Radetti, G., Beck-Peccoz, P., Zhu, H., Davis, T. M. E., Sun, Y., Corssmit, E. P., Appelman-Dijkstra, N. M., Heinen, C. A., Pereira, A. M., Varewijck, A. J., Janssen, J. A. M. J. L., Endert, E., Hennekam, R. C., Lombardi, M. P., Mannens, M. M. A. M., Bak, B., Bernard, D. J., Breuning, M. H., Chatterjee, K., Dattani, M. T., Oostdijk, W., Biermasz, N. R., Wit, J. M., and van Trotsenburg, A. S. P.

Published
2013

11. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Author

Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, Y, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, S-Y, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, C, Yang, J, Zhang, F, Zhang, P, Zheng, H-F, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B, UK10K Consortium, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, and Child and Adolescent Psychiatry / Psychology

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Published
2019

12. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Author

Haworth, S., Shapland, C.Y., Hayward, C. (Caroline), Prins, B.P. (Bram), Felix, J.F. (Janine), Medina-Gomez, M.C. (Carolina), Rivadeneira Ramirez, F. (Fernando), Wang, C., Ahluwalia, TS, Vrijheid, M. (Martine), Guxens Junyent, M. (Mònica), Sunyer, J. (Jordi), Tachmazidou, I, Walter, K., Iotchkova, V, Jackson, A.U. (Anne), Cleal, L., Huffmann, J., Min, J. (Josine), Sass, L., Timmers, P, Al Turki, S., Anderson, CA, Anney, R. (Richard), Antony, D, Soler Artigas, M. (Maria), Ayub, M, Bala, S, Barrett, JC, Barroso, I.E. (Inês), Beales, P., Bentham, J, Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G. (Gerome), Calissano, M, Carss, K, Charlton, R, Chatterjee, K. (Krishna), Chen, L. (Leslie), Ciampi, A. (Antonio), Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, D.A. (David), Cosgrove, C, Cox, T. (Tessa), Craddock, N.J. (Nick), Crooks, L, Curran, S, Curtis, D. (David), Daly, A, Danecek, P, Day, I.N.M. (Ian), Day-Williams, A, Dominiczak, A. (Anna), Down, T, Li, Y. (Yingrui), Dunham, D.M. (David), Durbin, R, Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Paul), Evans, D.M. (David), Farooqi, I.S. (Sadaf), Fitzpatrick, D.R. (David), Flicek, P, Floyd, J. (Jamie), Foley, AR, Franklin, C.S. (Christopher), Futema, M, Gallagher, L. (Louise), Gaunt, T.R. (Tom), Geihs, M, Geschwind, D., Greenwood, J.P. (John), Griffin, H, Grozeva, D. (Detelina), Guo, X.S., Guo, X. (Xiuqing), Gurling, H. (Hugh), Hart, D.J. (Deborah), Hendricks, AE, Holmans, P.A. (Peter), Howie, B, Huang, J. (Jian), Huang, L.R., Hubbard, T., Humphries, S.E. (Steve), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Jackson, DK, Jamshidi, Y. (Yalda), Joyce, C, Karczewski, KJ, Kaye, J. (Jane), Keane, T, Kemp, J.P., Kennedy, K. (Karen), Kent, A. (Alistair), Keogh, J, Khawaja, F, van Kogelenberg, M., Kolb-Kokocinski, A, Lachance, G, Langford, C. (Cordelia), Lawson, D, Lee, I. van der, Lek, M, Li, R. (Rui), Li, Y.R. (Yun), Liang, J.Q., Lin, H., Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M., MacArthur, DG, Mangino, M. (Massimo), Marchini, J. (Jonathan), Marenne, G., Maslen, J., Mathieson, I. (Iain), McCarthy, S. (Sean), Mcguffin, P. (Peter), Mcintosh, A.M. (Andrew), McKechanie, AG, McQuillin, A. (Andrew), Memari, Y, Metrustry, S. (Sarah), Migone, N, Mitchison, H.M. (Hannah), Moayyeri, A. (Alireza), Morris, A.D. (Andrew), Morris, J, Muddyman, D, Muntoni, F., Northstone, K. (Kate), O'Donovan, M. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A, Oualkacha, K., Owen, M.J., Palotie, A. (Aarno), Panoutsopoulou, K, Parker, V., Parr, D., Paternoster, L. (Lavinia), Paunio, T, Payne, F. (Felicity), Payne, SJ, Perry, J.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V, Pollitt, RC, Porteous, D.J. (David J.), Povey, S. (Sue), Quail, MA, Quaye, L. (Lydia), Raymond, FL, Rehnström, K. (Karola), Richards, J.B. (Brent), Ridout, CK, Ring, S.M. (Susan), Ritchie, GRS, Roberts, N. (Nicola), Robinson, RL, Savage, D.B. (David), Scambler, P., Schiffels, S, Schmidts, M, Schoenmakers, N. (Nadia), Scott, RH, Semple, R.K. (Robert), Serra, E, Sharp, S.I., Shaw, A. (Alison), Shihab, HA, Shin, S.-Y., Skuse, D, Small, K.S. (Kerrin), Smee, C, Smith, B.H. (Blair), Soranzo, N. (Nicole), Southam, L. (Lorraine), Spasic-Boskovic, O, Spector, T.D. (Timothy), St. Clair, D. (David), Stalker, J, Stevens, E, Sun, J.P., Surdulescu, G, Suvisaari, J. (Jaana), Syrris, P, R. Taylor (Rohan), Tian, J., Tobin, M.D. (Martin), Valdes, A.M. (Ana Maria), Vandersteen, AM, Vijayarangakannan, P, Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, JTR, Wang, G. B., Wang, J. (Jinxia), Wang, Y. (Ying), Ward, K, Wheeler, E. (Eleanor), Whyte, T, Williams, HJ, Williamson, K.A., Wilson, C, Wilson, S.G. (Scott), Wong, K. (Kenny), Xu, CJ, Yang, J. (Jian), Zhang, F. (Feng), Zhang, P.B., Zheng, H.-F. (Hou-Feng), Smith, A.V. (Davey), Fisher, SE, Wilson, J.F. (James F), Cole, T.J. (T.), Fernandez-Orth, D., Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Jaddoe, V.W.V. (Vincent), Dedoussis, G, Timpson, N.J. (Nicholas), Zeggini, E. (Eleftheria), Vitart, V. (Veronique), Pourcain, B.S. (Beate), Haworth, S., Shapland, C.Y., Hayward, C. (Caroline), Prins, B.P. (Bram), Felix, J.F. (Janine), Medina-Gomez, M.C. (Carolina), Rivadeneira Ramirez, F. (Fernando), Wang, C., Ahluwalia, TS, Vrijheid, M. (Martine), Guxens Junyent, M. (Mònica), Sunyer, J. (Jordi), Tachmazidou, I, Walter, K., Iotchkova, V, Jackson, A.U. (Anne), Cleal, L., Huffmann, J., Min, J. (Josine), Sass, L., Timmers, P, Al Turki, S., Anderson, CA, Anney, R. (Richard), Antony, D, Soler Artigas, M. (Maria), Ayub, M, Bala, S, Barrett, JC, Barroso, I.E. (Inês), Beales, P., Bentham, J, Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G. (Gerome), Calissano, M, Carss, K, Charlton, R, Chatterjee, K. (Krishna), Chen, L. (Leslie), Ciampi, A. (Antonio), Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, D.A. (David), Cosgrove, C, Cox, T. (Tessa), Craddock, N.J. (Nick), Crooks, L, Curran, S, Curtis, D. (David), Daly, A, Danecek, P, Day, I.N.M. (Ian), Day-Williams, A, Dominiczak, A. (Anna), Down, T, Li, Y. (Yingrui), Dunham, D.M. (David), Durbin, R, Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Paul), Evans, D.M. (David), Farooqi, I.S. (Sadaf), Fitzpatrick, D.R. (David), Flicek, P, Floyd, J. (Jamie), Foley, AR, Franklin, C.S. (Christopher), Futema, M, Gallagher, L. (Louise), Gaunt, T.R. (Tom), Geihs, M, Geschwind, D., Greenwood, J.P. (John), Griffin, H, Grozeva, D. (Detelina), Guo, X.S., Guo, X. (Xiuqing), Gurling, H. (Hugh), Hart, D.J. (Deborah), Hendricks, AE, Holmans, P.A. (Peter), Howie, B, Huang, J. (Jian), Huang, L.R., Hubbard, T., Humphries, S.E. (Steve), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Jackson, DK, Jamshidi, Y. (Yalda), Joyce, C, Karczewski, KJ, Kaye, J. (Jane), Keane, T, Kemp, J.P., Kennedy, K. (Karen), Kent, A. (Alistair), Keogh, J, Khawaja, F, van Kogelenberg, M., Kolb-Kokocinski, A, Lachance, G, Langford, C. (Cordelia), Lawson, D, Lee, I. van der, Lek, M, Li, R. (Rui), Li, Y.R. (Yun), Liang, J.Q., Lin, H., Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M., MacArthur, DG, Mangino, M. (Massimo), Marchini, J. (Jonathan), Marenne, G., Maslen, J., Mathieson, I. (Iain), McCarthy, S. (Sean), Mcguffin, P. (Peter), Mcintosh, A.M. (Andrew), McKechanie, AG, McQuillin, A. (Andrew), Memari, Y, Metrustry, S. (Sarah), Migone, N, Mitchison, H.M. (Hannah), Moayyeri, A. (Alireza), Morris, A.D. (Andrew), Morris, J, Muddyman, D, Muntoni, F., Northstone, K. (Kate), O'Donovan, M. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A, Oualkacha, K., Owen, M.J., Palotie, A. (Aarno), Panoutsopoulou, K, Parker, V., Parr, D., Paternoster, L. (Lavinia), Paunio, T, Payne, F. (Felicity), Payne, SJ, Perry, J.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V, Pollitt, RC, Porteous, D.J. (David J.), Povey, S. (Sue), Quail, MA, Quaye, L. (Lydia), Raymond, FL, Rehnström, K. (Karola), Richards, J.B. (Brent), Ridout, CK, Ring, S.M. (Susan), Ritchie, GRS, Roberts, N. (Nicola), Robinson, RL, Savage, D.B. (David), Scambler, P., Schiffels, S, Schmidts, M, Schoenmakers, N. (Nadia), Scott, RH, Semple, R.K. (Robert), Serra, E, Sharp, S.I., Shaw, A. (Alison), Shihab, HA, Shin, S.-Y., Skuse, D, Small, K.S. (Kerrin), Smee, C, Smith, B.H. (Blair), Soranzo, N. (Nicole), Southam, L. (Lorraine), Spasic-Boskovic, O, Spector, T.D. (Timothy), St. Clair, D. (David), Stalker, J, Stevens, E, Sun, J.P., Surdulescu, G, Suvisaari, J. (Jaana), Syrris, P, R. Taylor (Rohan), Tian, J., Tobin, M.D. (Martin), Valdes, A.M. (Ana Maria), Vandersteen, AM, Vijayarangakannan, P, Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, JTR, Wang, G. B., Wang, J. (Jinxia), Wang, Y. (Ying), Ward, K, Wheeler, E. (Eleanor), Whyte, T, Williams, HJ, Williamson, K.A., Wilson, C, Wilson, S.G. (Scott), Wong, K. (Kenny), Xu, CJ, Yang, J. (Jian), Zhang, F. (Feng), Zhang, P.B., Zheng, H.-F. (Hou-Feng), Smith, A.V. (Davey), Fisher, SE, Wilson, J.F. (James F), Cole, T.J. (T.), Fernandez-Orth, D., Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Jaddoe, V.W.V. (Vincent), Dedoussis, G, Timpson, N.J. (Nicholas), Zeggini, E. (Eleftheria), Vitart, V. (Veronique), and Pourcain, B.S. (Beate)

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for lowfrequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carrie

Published
2019
Full Text
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13. Negative cognitions of dental phobics: reliability and validity of the dental cognitions questionnaire

Author

Jongh, A. de, Muris, P., Schoenmakers, N., and Ter Horst, G.

Subjects
Dentist and patient -- Research, Phobias -- Diagnosis, Personality questionnaires -- Evaluation, Psychology and mental health
Abstract

This study investigated the psychometric properties of the Dental Cognitions Questionnaire (DCQ). This measure contains 38 items and assesses both frequency and believability of negative cognitions related to dental treatment. The results indicated that the DCQ has good internal consistency, high test-retest reliability, and satisfactory concurrent validity, as indicated by positive associations with indices of anxiety and other cognitive measures (n = 180). Factor analysis revealed a one factor solution. Furthermore, the DCQ discriminated strongly between dental phobics (n = 85) and non-phobic Ss (n = 70). Moreover, it was found that combinations of DCQ items have substantially more explanatory power than did a measure of dental trait anxiety, explaining up to 70.7% of the variance in state anxiety ratings in the dental situation. Overall, it appears that dental phobics have many extremely negative beliefs and self-statements about themselves and about what might happen during treatment. Since certain cognitions seem to play a critical role in fear evocation, diminishing catastrophizing ideation may be an important determinant of adjustment to dental treatment and reduction of psychological distress.

Published
1995

14. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland

Author

Nicholas, AK, Jaleel, S, Lyons, G, Schoenmakers, E, Dattani, MT, Crowne, E, Bernhard, B, Kirk, J, Roche, EF, Chatterjee, VK, Schoenmakers, N, Schoenmakers, Erik [0000-0003-0674-8282], Chatterjee, Krishna [0000-0002-2654-8854], Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository

Subjects
Male, Heterozygote, Delayed Diagnosis, Homozygote, Infant, Newborn, Original Articles, Sequence Analysis, DNA, Thyrotropin, beta Subunit, United Kingdom, Pedigree, Editor's Choice, Neonatal Screening, Hypothyroidism, Congenital Hypothyroidism, Humans, Original Article, Female, Ireland
Abstract

Summary Objective Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH‐based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. Design, Patients and Measurements Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). Results Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4‐kB TSHB deletion (kindred 2, c.1‐4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. Conclusions This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine‐binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.

Published
2016

16. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

Author

Cangul, H. (Hakan), Liao, X.-H. (Xiao-Hui), Schoenmakers, E. (Erik), Kero, J. (Jukka), Barone, S. (Sharon), Srichomkwun, P. (Panudda), Iwayama, H. (Hideyuki), Serra, E. G. (Eva G.), Saglam, H. (Halil), Eren, E. (Erdal), Tarim, O. (Omer), Nicholas, A. K. (Adeline K.), Zvetkova, I. (Ilona), Anderson, C. A. (Carl A.), Frankl, F. E. (Fiona E. Karet), Boelaert, K. (Kristien), Ojaniemi, M. (Marja), Jääskeläinen, J. (Jarmo), Patyra, K. (Konrad), Löf, C. (Christoffer), Williams, E. D. (E. Dillwyn), UK10K Consortium, . (), Soleimani, M. (Manoocher), Barrett, T. (Timothy), Maher, E. R. (Eamonn R.), Chatterjee, V. K. (V. Krishna), Refetoff, S. (Samuel), Schoenmakers, N. (Nadia), Cangul, H. (Hakan), Liao, X.-H. (Xiao-Hui), Schoenmakers, E. (Erik), Kero, J. (Jukka), Barone, S. (Sharon), Srichomkwun, P. (Panudda), Iwayama, H. (Hideyuki), Serra, E. G. (Eva G.), Saglam, H. (Halil), Eren, E. (Erdal), Tarim, O. (Omer), Nicholas, A. K. (Adeline K.), Zvetkova, I. (Ilona), Anderson, C. A. (Carl A.), Frankl, F. E. (Fiona E. Karet), Boelaert, K. (Kristien), Ojaniemi, M. (Marja), Jääskeläinen, J. (Jarmo), Patyra, K. (Konrad), Löf, C. (Christoffer), Williams, E. D. (E. Dillwyn), UK10K Consortium, . (), Soleimani, M. (Manoocher), Barrett, T. (Timothy), Maher, E. R. (Eamonn R.), Chatterjee, V. K. (V. Krishna), Refetoff, S. (Samuel), and Schoenmakers, N. (Nadia)

Abstract

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation.SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

Published
2018

17. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, A.E. Bochukova, E.G. Marenne, G. Keogh, J.M. Atanassova, N. Bounds, R. Wheeler, E. Mistry, V. Henning, E. Körner, A. Muddyman, D. McCarthy, S. Hinney, A. Hebebrand, J. Scott, R.A. Langenberg, C. Wareham, N.J. Surendran, P. Howson, J.M. Butterworth, A.S. Danesh, J. Nordestgaard, Bø.G. Nielsen, S.F. Afzal, S. Papadia, S. Ashford, S. Garg, S. Millhauser, G.L. Palomino, R.I. Kwasniewska, A. Tachmazidou, I. O'Rahilly, S. Zeggini, E. Barroso, I. Farooqi, I.S. Benzeval, M. Burton, J. Buck, N. Jäckle, A. Kumari, M. Laurie, H. Lynn, P. Pudney, S. Rabe, B. Wolke, D. Overvad, K. Tjønneland, A. Clavel-Chapelon, F. Kaaks, R. Boeing, H. Trichopoulou, A. Ferrari, P. Palli, D. Krogha, V. Panico, S. Tuminoa, R. Matullo, G. Boer, J. Van Der Schouw, Y. Weiderpass, E. Quiros, J.R. Sánchez, M.-J. Navarro, C. Moreno-Iribas, C. Arriola, L. Melander, O. Wennberg, P. Key, T.J. Riboli, E. Turki, S.A. Anderson, C.A. Anney, R. Antony, D. Soler Artigas, M. Ayub, M. Bala, S. Barrett, J.C. Beales, P. Bentham, J. Bhattacharyaa, S. Birney, E. Blackwooda, D. Bobrow, M. Bolton, P.F. Boustred, C. Breen, G. Calissanoa, M. Carss, K. Charlton, R. Chatterjee, K. Chen, L. Ciampia, A. Cirak, S. Clapham, P. Clement, G. Coates, G. Coccaa, M. Collier, D.A. Cosgrove, C. Coxa, T. Craddock, N. Crooks, L. Curran, S. Curtis, D. Daly, A. Danecek, P. Day, I.N.M. Day-Williams, A. Dominiczak, A. Down, T. Du, Y. Dunham, I. Durbin, R. Edkins, S. Ekong, R. Ellis, P. Evansa, D.M. Fitzpatrick, D.R. Flicek, P. Floyd, J. Foley, A.R. Franklin, C.S. Futema, M. Gallagher, L. Gaunt, T.R. Geihs, M. Geschwind, D. Greenwood, C.M.T. Griffin, H. Grozeva, D. Guo, X. Guo, X. Gurling, H. Hart, D. Holmans, P. Howie, B. Huang, J. Huang, L. Hubbard, T. Humphries, S.E. Hurles, M.E. Hysi, P. Iotchkova, V. Jackson, D.K. Jamshidi, Y. Joyce, C. Karczewski, K.J. Kaye, J. Keane, T. Kemp, J.P. Kennedy, K. Kent, A. Khawaja, F. Van Kogelenberg, M. Kolb-Kokocinski, A. Lachance, G. Langford, C. Lawson, D. Lee, I. Lek, M. Li, R. Li, Y. Liang, J. Lin, H. Liu, R. Lönnqvist, J. Lopes, L.R. Lopes, M. MacArthur, D.G. Mangino, M. Marchini, J. Maslen, J. Mathieson, I. McGuffin, P. McIntosh, A.M. McKechanie, A.G. McQuillin, A. Memari, Y. Metrustry, S. Migone, N. Min, J.L. Mitchison, H.M. Moayyeri, A. Morris, A. Morris, J. Muntoni, F. Northstone, K. O'Donovan, M.C. Onoufriadis, A. Oualkacha, K. Owen, M.J. Palotie, A. Panoutsopoulou, K. Parker, V. Parr, J.R. Paternoster, L. Paunio, T. Payne, F. Payne, S.J. Perry, J.R.B. Pietilainen, O. Plagnol, V. Pollitt, R.C. Porteous, D.J. Povey, S. Quail, M.A. Quaye, L. Raymond, F.L. Rehnström, K. Richards, J.B. Ridout, C.K. Ring, S. Ritchie, G.R.S. Roberts, N. Robinson, R.L. Savage, D.B. Scambler, P. Schiffels, S. Schmidts, M. Schoenmakers, N. Scott, R.H. Semple, R.K. Serra, E. Sharp, S.I. Shaw, A. Shihab, H.A. Shin, S.-Y. Skuse, D. Small, K.S. Smee, C. Smith, B.H. Davey Smith, G. Soranzo, N. Southam, L. Spasic-Boskovic, O. Spector, T.D. St Clair, D. St Pourcain, B. Stalker, J. Stevens, E. Sun, J. Surdulescu, G. Suvisaari, J. Syrris, P. Taylor, R. Tian, J. Timpson, N.J. Tobin, M.D. Valdes, A.M. Vandersteen, A.M. Vijayarangakannan, P. Visscher, P.M. Wain, L.V. Walter, K. Walters, J.T.R. Wang, G. Wang, J. Wang, Y. Ward, K. Whyte, T. Williams, H.J. Williamson, K.A. Wilson, C. Wilson, S.G. Wong, K. Xu, C. Yang, J. Zhang, F. Zhang, P. Zheng, H.-F.

Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. © 2017 The Author(s).

Published
2017

18. IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management

Author

Joustra, S.D., Heinen, C.A., Schoenmakers, N., Bonomi, M., Ballieux, B.E.P.B., Turgeon, M.O., Bernard, D.J., Fliers, E., Trotsenburg, A.S.P. van, Losekoot, M., Persani, L., Wit, J.M., Biermasz, N.R., Pereira, A.M., Oostdijk, W., IGSF Clinical Care Grp, Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Adolescent, Immunoglobulins, Infant, Membrane Proteins, Genetic Diseases, X-Linked, Syndrome, Middle Aged, Neuropsychological Tests, Thyroxine, Young Adult, Hypothyroidism, Attention Deficit Disorder with Hyperactivity, Child, Preschool, Practice Guidelines as Topic, Quality of Life, Humans, Female, Child, Aged
Abstract

CONTEXT: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. OBJECTIVE: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. METHODS: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. RESULTS: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. CONCLUSION: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Published
2016

19. IGSF1 Deficiency

Author

IGSF1 Clinical Care Group, Joustra, S D, Heinen, C A, Schoenmakers, N, Bonomi, M, Ballieux, B E P B, Turgeon, M-O, Bernard, D J, Fliers, E, van Trotsenburg, A S P, Losekoot, M, Persani, L, Wit, J M, Biermasz, N R, Pereira, A M, Oostdijk, W, De Schepper, Jean, Mental Health and Wellbeing research group, Clinical sciences, Biology of the Testis, and Pediatrics

Subjects
Adult, Male, Adolescent, Child, preschool, Membrane Proteins/deficiency, Hypothyroidism/drug therapy, Infant, Attention Deficit Disorder with Hyperactivity/drug therapy, Middle Aged, Neuropsychological Tests, syndrome, Genetic Diseases, X-Linked/drug therapy, Thyroxine/therapeutic use, Humans, Immunoglobulins/deficiency, young adult, Female, Practice Guidelines as Topic/standards, aged, 80 and over, Child, Quality Of Life, Aged
Abstract

CONTEXT: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. OBJECTIVE: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. METHODS: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. RESULTS: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. CONCLUSION: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Published
2016

20. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Author

Huang, J, Howie, B, Mccarthy, S, Memari, Y, Walter, K, Min, Jl, Danecek, P, Malerba, Giovanni, Trabetti, Elisabetta, Zheng, Hf, Gambaro, G, Richards, Jb, Durbin, R, Timpson, Nj, Marchini, J, Soranzo, N, Al Turki, S, Amuzu, A, Anderson, Ca, Anney, R, Antony, D, Artigas, Ms, Ayub, M, Bala, S, Barrett, Jc, Barroso, I, Beales, P, Benn, M, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, Pf, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Casas, Jp, Chambers, Jc, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, Da, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Day, In, Day Williams, A, Dedoussis, G, Down, T, Du, Y, van Duijn, Cm, Dunham, I, Edkins, S, Ekong, R, Ellis, P, Evans, Dm, Farooqi, Is, Fitzpatrick, Dr, Flicek, P, Floyd, J, Foley, Ar, Franklin, Cs, Futema, M, Gallagher, L, Gasparini, P, Gaunt, Tr, Geihs, M, Geschwind, D, Greenwood, C, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, Ae, Holmans, P, Huang, L, Hubbard, T, Humphries, Se, Hurles, Me, Hysi, P, Iotchkova, V, Isaacs, A, Jackson, Dk, Jamshidi, Y, Johnson, J, Joyce, C, Karczewski, Kj, Kaye, J, Keane, T, Kemp, Jp, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, Kleber, Me, van Kogelenberg, M, Kolb Kokocinski, A, Kooner, Js, Lachance, G, Langenberg, C, Langford, C, Lawson, D, Lee, I, van Leeuwen, Em, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lönnqvist, J, Lopes, Lr, Lopes, M, Luan, J, Macarthur, Dg, Mangino, M, Marenne, G, März, W, Maslen, J, Matchan, A, Mathieson, I, Mcguffin, P, Mcintosh, Am, Mckechanie, Ag, Mcquillin, A, Metrustry, S, Migone, N, Mitchison, Hm, Moayyeri, A, Morris, J, Morris, R, Muddyman, D, Muntoni, F, Nordestgaard, Bg, Northstone, K, O'Donovan, Mc, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, Mj, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, Jr, Paternoster, L, Paunio, T, Payne, F, Payne, Sj, Perry, Jr, Pietilainen, O, Plagnol, V, Pollitt, Rc, Povey, S, Quail, Ma, Quaye, L, Raymond, L, Rehnström, K, Ridout, Ck, Ring, S, Ritchie, Gr, Roberts, N, Robinson, Rl, Savage, Db, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, Rh, Scott, Ra, Semple, Rk, Serra, E, Sharp, Si, Shaw, A, Shihab, Ha, Shin, Sy, Skuse, D, Small, Ks, Smee, C, Smith, Gd, Southam, L, Spasic Boskovic, O, Spector, Td, St Clair, D, St Pourcain, B, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Tachmazidou, I, Taylor, R, Tian, J, Tobin, Md, Toniolo, D, Traglia, M, Tybjaerg Hansen, A, Valdes, Am, Vandersteen, Am, Varbo, A, Vijayarangakannan, P, Visscher, Pm, Wain, Lv, Walters, Jt, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whincup, P, Whyte, T, Williams, Hj, Williamson, Ka, Wilson, C, Wilson, Sg, Wong, K, Xu, C, Yang, J, Zaza, Gianluigi, Zeggini, E, Zhang, F, Zhang, P, Zhang, W., Clinicum, Department of Psychiatry, Jie, Huang, Bryan, Howie, Shane, Mccarthy, Yasin, Memari, Klaudia, Walter, Josine L., Min, Petr, Danecek, Giovanni, Malerba, Elisabetta, Trabetti, Hou Feng, Zheng, Saeed Al, Turki, Antoinette, Amuzu, Carl A., Anderson, Richard, Anney, Dinu, Antony, María Soler, Artiga, Muhammad, Ayub, Senduran, Bala, Jeffrey C., Barrett, Inês, Barroso, Phil, Beale, Marianne, Benn, Jamie, Bentham, Shoumo, Bhattacharya, Ewan, Birney, Douglas, Blackwood, Martin, Bobrow, Elena, Bochukova, Patrick F., Bolton, Rebecca, Bound, Chris, Boustred, Gerome, Breen, Mattia, Calissano, Keren, Car, Juan Pablo, Casa, John C., Chamber, Ruth, Charlton, Krishna, Chatterjee, Lu, Chen, Antonio, Ciampi, Sebahattin, Cirak, Peter, Clapham, Gail, Clement, Guy, Coate, Cocca, Massimiliano, David A., Collier, Catherine, Cosgrove, Tony, Cox, Nick, Craddock, Lucy, Crook, Sarah, Curran, David, Curti, Allan, Daly, Ian N. M., Day, Aaron Day, William, George, Dedoussi, Thomas, Down, Yuanping, Du, Cornelia M., van Duijn, Ian, Dunham, Sarah, Edkin, Rosemary, Ekong, Peter, Elli, David M., Evan, I., Sadaf Farooqi, David R., Fitzpatrick, Paul, Flicek, James, Floyd, A., Reghan Foley, Christopher S., Franklin, Marta, Futema, Louise, Gallagher, Gasparini, Paolo, Tom R., Gaunt, Matthias, Geih, Daniel, Geschwind, Celia, Greenwood, Heather, Griffin, Detelina, Grozeva, Xiaosen, Guo, Xueqin, Guo, Hugh, Gurling, Deborah, Hart, Audrey E., Hendrick, Peter, Holman, Liren, Huang, Tim, Hubbard, Steve E., Humphrie, Matthew E., Hurle, Pirro, Hysi, Valentina, Iotchkova, Aaron, Isaac, David K., Jackson, Yalda, Jamshidi, Jon, Johnson, Chris, Joyce, Konrad J., Karczewski, Jane, Kaye, Thomas, Keane, John P., Kemp, Karen, Kennedy, Alastair, Kent, Julia, Keogh, Farrah, Khawaja, Marcus E., Kleber, Margriet van, Kogelenberg, Anja Kolb, Kokocinski, Jaspal S., Kooner, Genevieve, Lachance, Claudia, Langenberg, Cordelia, Langford, Daniel, Lawson, Irene, Lee, Elisabeth M., van Leeuwen, Monkol, Lek, Rui, Li, Yingrui, Li, Jieqin, Liang, Hong, Lin, Ryan, Liu, Jouko, Lönnqvist, Luis R., Lope, Margarida, Lope, Jian'An, Luan, Daniel G., Macarthur, Massimo, Mangino, Gaëlle, Marenne, Winfried, März, John, Maslen, Angela, Matchan, Iain, Mathieson, Peter, Mcguffin, Andrew M., Mcintosh, Andrew G., Mckechanie, Andrew, Mcquillin, Sarah, Metrustry, Nicola, Migone, Hannah M., Mitchison, Alireza, Moayyeri, James, Morri, Richard, Morri, Dawn, Muddyman, Francesco, Muntoni, Børge G., Nordestgaard, Kate, Northstone, Michael C., O'Donovan, Stephen, O'Rahilly, Alexandros, Onoufriadi, Karim, Oualkacha, Michael J., Owen, Aarno, Palotie, Kalliope, Panoutsopoulou, Victoria, Parker, Jeremy R., Parr, Lavinia, Paternoster, Tiina, Paunio, Felicity, Payne, Stewart J., Payne, John R. B., Perry, Olli, Pietilainen, Vincent, Plagnol, Rebecca C., Pollitt, Sue, Povey, Michael A., Quail, Lydia, Quaye, Lucy, Raymond, Karola, Rehnström, Cheryl K., Ridout, Susan, Ring, Graham R. S., Ritchie, Nicola, Robert, Rachel L., Robinson, David B., Savage, Peter, Scambler, Stephan, Schiffel, Miriam, Schmidt, Nadia, Schoenmaker, Richard H., Scott, Robert A., Scott, Robert K., Semple, Eva, Serra, Sally I., Sharp, Adam, Shaw, Hashem A., Shihab, So Youn, Shin, David, Skuse, Kerrin S., Small, Carol, Smee, George Davey, Smith, Lorraine, Southam, Olivera Spasic, Boskovic, Timothy D., Spector, David St, Clair, Beate St, Pourcain, Jim, Stalker, Elizabeth, Steven, Jianping, Sun, Gabriela, Surdulescu, Jaana, Suvisaari, Petros, Syrri, Ioanna, Tachmazidou, Rohan, Taylor, Jing, Tian, Martin D., Tobin, Daniela, Toniolo, Michela, Traglia, Anne Tybjaerg, Hansen, Ana M., Valde, Anthony M., Vandersteen, Anette, Varbo, Parthiban, Vijayarangakannan, Peter M., Visscher, Louise V., Wain, James T. R., Walter, Guangbiao, Wang, Jun, Wang, Yu, Wang, Kirsten, Ward, Eleanor, Wheeler, Peter, Whincup, Tamieka, Whyte, Hywel J., William, Kathleen A., Williamson, Crispian, Wilson, Scott G., Wilson, Kim, Wong, Changjiang, Xu, Jian, Yang, Gianluigi, Zaza, Eleftheria, Zeggini, Feng, Zhang, Pingbo, Zhang, Weihua, Zhang, Giovanni, Gambaro, J., Brent Richard, Richard, Durbin, Nicholas J., Timpson, Jonathan, Marchini, and Nicole, Soranzo

Subjects
Computer science, General Physics and Astronomy, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Haplotype, Genetics,Biological sciences, Settore MED/14 - NEFROLOGIA, Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, TWINSUK, Middle Aged, single-nucleotide polymorphism, Whole-genome sequencing, WGS imputation panel, single-nucleotide polymorphism, Biological sciences, Italy, MAP, Adult, Adolescent, Genotype, WGS imputation panel, Population, Single-nucleotide polymorphism, FORMAT, Computational biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Humans, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, education, Allele frequency, Alleles, Aged, 030304 developmental biology, Whole-genome sequencing, Models, Statistical, Models, Genetic, Genome, Human, Genetic Variation, General Chemistry, United Kingdom, Minor allele frequency, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Haplotypes, 3111 Biomedicine, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants., Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Published
2015

21. Congenital hypothyroidism: update and perspectives.

Author

Peters, C., van Trotsenburg, A. S. P., and Schoenmakers, N.

Subjects
CONGENITAL hypothyroidism, THYROTROPIN, HORMONE synthesis
Abstract

Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH. [ABSTRACT FROM AUTHOR]

Published
2018
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22. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Author

Huang, J. (Jie), Howie, B. (Bryan), McCarthy, S. (Shane), Memari, Y. (Yasin), Walter, K. (Klaudia), Min, J.L. (Josine L.), Danecek, P. (Petr), Malerba, G. (Giovanni), Trabetti, E. (Elisabetta), Zheng, H.-F. (Hou-Feng), Gambaro, G. (Giovanni), Richards, J.B. (Brent), Durbin, R. (Richard), Timpson, N.J. (Nicholas), Marchini, J. (Jonathan), Soranzo, N. (Nicole), Al Turki, S.H. (Saeed), Amuzu, A. (Antoinette), Anderson, C. (Carl), Anney, R. (Richard), Antony, D. (Dinu), Artigas, M.S., Ayub, M. (Muhammad), Bala, S. (Senduran), Barrett, J.C. (Jeffrey), Barroso, I.E. (Inês), Beales, P.L. (Philip), Benn, M. (Marianne), Bentham, J. (Jamie), Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D.H.R. (Douglas), Bobrow, M. (Martin), Bochukova, E. (Elena), Bolton, P.F. (Patrick F.), Bounds, R. (Rebecca), Boustred, C. (Chris), Breen, G. (Gerome), Calissano, M. (Mattia), Carss, K. (Keren), Casas, J.P. (Juan Pablo), Chambers, J.C. (John C.), Charlton, R. (Ruth), Chatterjee, K. (Krishna), Chen, L. (Lu), Ciampi, A. (Antonio), Cirak, S. (Sebahattin), Clapham, P. (Peter), Clement, G. (Gail), Coates, G. (Guy), Cocca, M. (Massimiliano), Collier, D.A. (David), Cosgrove, C. (Catherine), Cox, T. (Tony), Craddock, N.J. (Nick), Crooks, L. (Lucy), Curran, S. (Sarah), Curtis, D. (David), Daly, A. (Allan), Day, I.N.M. (Ian N.M.), Day-Williams, A.G. (Aaron), Dedoussis, G.V. (George), Down, T. (Thomas), Du, Y. (Yuanping), Duijn, C.M. (Cornelia) van, Dunham, I. (Ian), Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Peter), Evans, D.M. (David), Farooqi, I.S. (I. Sadaf), Fitzpatrick, D.R. (David R.), Flicek, P. (Paul), Floyd, J. (James), Foley, A.R. (A. Reghan), Franklin, C.S. (Christopher S.), Futema, M. (Marta), Gallagher, L. (Louise), Gasparini, P. (Paolo), Gaunt, T.R. (Tom), Geihs, M. (Matthias), Geschwind, D. (Daniel), Greenwood, C.M.T. (Celia), Griffin, H. (Heather), Grozeva, D. (Detelina), Guo, X. (Xiaosen), Guo, X. (Xueqin), Gurling, H. (Hugh), Hart, D. (Deborah), Hendricks, A.E. (Audrey E.), Holmans, P.A. (Peter A.), Huang, L. (Liren), Hubbard, T. (Tim), Humphries, S.E. (Steve E.), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Iotchkova, V. (Valentina), Isaacs, A. (Aaron), Jackson, D.K. (David K.), Jamshidi, Y. (Yalda), Johnson, J. (Jon), Joyce, C. (Chris), Karczewski, K.J. (Konrad), Kaye, J. (Jane), Keane, T. (Thomas), Kemp, J.P. (John), Kennedy, K. (Karen), Kent, A. (Alastair), Keogh, J. (Julia), Khawaja, F. (Farrah), Kleber, M.E. (Marcus), Van Kogelenberg, M. (Margriet), Kolb-Kokocinski, A. (Anja), Kooner, J.S. (Jaspal S.), Lachance, G. (Genevieve), Langenberg, C. (Claudia), Langford, C. (Cordelia), Lawson, D. (Daniel), Lee, I. (Irene), Leeuwen, E.M. (Elisa) van, Lek, M. (Monkol), Li, R. (Rui), Li, Y. (Yingrui), Liang, J. (Jieqin), Lin, H. (Hong), Liu, R. (Ryan), Lönnqvist, J. (Jouko), Lopes, L.R. (Luis R.), Lopes, M.C. (Margarida), Luan, J., MacArthur, D.G. (Daniel G.), Mangino, M. (Massimo), Marenne, G. (Gaëlle), März, W. (Winfried), Maslen, J. (John), Matchan, A. (Angela), Mathieson, I. (Iain), McGuffin, P. (Peter), McIntosh, A.M. (Andrew), McKechanie, A.G. (Andrew G.), McQuillin, A. (Andrew), Metrustry, S. (Sarah), Migone, N. (Nicola), Mitchison, H.M. (Hannah M.), Moayyeri, A. (Alireza), Morris, J. (James), Morris, R.W. (Richard), Muddyman, D. (Dawn), Muntoni, F., Nordestgaard, B.G. (Børge G.), Northstone, K. (Kate), O'donovan, M.C. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A. (Alexandros), Oualkacha, K. (Karim), Owen, M.J. (Michael J.), Palotie, A. (Aarno), Panoutsopoulou, K. (Kalliope), Parker, V. (Victoria), Parr, J.R. (Jeremy R.), Paternoster, L. (Lavinia), Paunio, T. (Tiina), Payne, F. (Felicity), Payne, S.J. (Stewart J.), Perry, J.R.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V. (Vincent), Pollitt, R.C. (Rebecca C.), Povey, S. (Sue), Quail, M.A. (Michael A.), Quaye, L. (Lydia), Raymond, L. (Lucy), Rehnström, K. (Karola), Ridout, C.K. (Cheryl K.), Ring, S.M. (Susan), Ritchie, G.R.S. (Graham R.S.), Roberts, N. (Nicola), Robinson, R.L. (Rachel L.), Savage, D.B. (David), Scambler, P.J. (Peter), Schiffels, S. (Stephan), Schmidts, M. (Miriam), Schoenmakers, N. (Nadia), Scott, R.H. (Richard H.), Scott, R.A. (Robert), Semple, R.K. (Robert K.), Serra, E. (Eva), Sharp, S.I. (Sally I.), Shaw, A.C. (Adam C.), Shihab, H.A. (Hashem A.), Shin, S.-Y. (So-Youn), Skuse, D. (David), Small, K.S. (Kerrin), Smee, C. (Carol), Smith, A.V. (Davey), Southam, L. (Lorraine), Spasic-Boskovic, O. (Olivera), Spector, T.D. (Timothy), St. Clair, D. (David), St Pourcain, B. (Beate), Stalker, J. (Jim), Stevens, E. (Elizabeth), Sun, J. (Jianping), Surdulescu, G. (Gabriela), Suvisaari, J. (Jaana), Syrris, P. (Petros), Tachmazidou, I. (Ioanna), Taylor, R. (Rohan), Tian, J. (Jing), Tobin, M.D. (Martin), Toniolo, D. (Daniela), Traglia, M. (Michela), Tybjaerg-Hansen, A. (Anne), Valdes, A.M., Vandersteen, A.M. (Anthony M.), Varbo, A. (Anette), Vijayarangakannan, P. (Parthiban), Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, J.T. (James), Wang, G. (Guangbiao), Wang, J. (Jun), Wang, Y. (Yu), Ward, K. (Kirsten), Wheeler, E. (Eleanor), Whincup, P.H. (Peter), Whyte, T. (Tamieka), Williams, H.J. (Hywel J.), Williamson, K.A. (Kathleen), Wilson, C. (Crispian), Wilson, S.G. (Scott), Wong, K. (Kim), Xu, C. (Changjiang), Yang, J. (Jian), Zaza, G. (Gianluigi), Zeggini, E. (Eleftheria), Zhang, F. (Feng), Zhang, P. (Pingbo), Zhang, W. (Weihua), Huang, J. (Jie), Howie, B. (Bryan), McCarthy, S. (Shane), Memari, Y. (Yasin), Walter, K. (Klaudia), Min, J.L. (Josine L.), Danecek, P. (Petr), Malerba, G. (Giovanni), Trabetti, E. (Elisabetta), Zheng, H.-F. (Hou-Feng), Gambaro, G. (Giovanni), Richards, J.B. (Brent), Durbin, R. (Richard), Timpson, N.J. (Nicholas), Marchini, J. (Jonathan), Soranzo, N. (Nicole), Al Turki, S.H. (Saeed), Amuzu, A. (Antoinette), Anderson, C. (Carl), Anney, R. (Richard), Antony, D. (Dinu), Artigas, M.S., Ayub, M. (Muhammad), Bala, S. (Senduran), Barrett, J.C. (Jeffrey), Barroso, I.E. (Inês), Beales, P.L. (Philip), Benn, M. (Marianne), Bentham, J. (Jamie), Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D.H.R. (Douglas), Bobrow, M. (Martin), Bochukova, E. (Elena), Bolton, P.F. (Patrick F.), Bounds, R. (Rebecca), Boustred, C. (Chris), Breen, G. (Gerome), Calissano, M. (Mattia), Carss, K. (Keren), Casas, J.P. (Juan Pablo), Chambers, J.C. (John C.), Charlton, R. (Ruth), Chatterjee, K. (Krishna), Chen, L. (Lu), Ciampi, A. (Antonio), Cirak, S. (Sebahattin), Clapham, P. (Peter), Clement, G. (Gail), Coates, G. (Guy), Cocca, M. (Massimiliano), Collier, D.A. (David), Cosgrove, C. (Catherine), Cox, T. (Tony), Craddock, N.J. (Nick), Crooks, L. (Lucy), Curran, S. (Sarah), Curtis, D. (David), Daly, A. (Allan), Day, I.N.M. (Ian N.M.), Day-Williams, A.G. (Aaron), Dedoussis, G.V. (George), Down, T. (Thomas), Du, Y. (Yuanping), Duijn, C.M. (Cornelia) van, Dunham, I. (Ian), Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Peter), Evans, D.M. (David), Farooqi, I.S. (I. Sadaf), Fitzpatrick, D.R. (David R.), Flicek, P. (Paul), Floyd, J. (James), Foley, A.R. (A. Reghan), Franklin, C.S. (Christopher S.), Futema, M. (Marta), Gallagher, L. (Louise), Gasparini, P. (Paolo), Gaunt, T.R. (Tom), Geihs, M. (Matthias), Geschwind, D. (Daniel), Greenwood, C.M.T. (Celia), Griffin, H. (Heather), Grozeva, D. (Detelina), Guo, X. (Xiaosen), Guo, X. (Xueqin), Gurling, H. (Hugh), Hart, D. (Deborah), Hendricks, A.E. (Audrey E.), Holmans, P.A. (Peter A.), Huang, L. (Liren), Hubbard, T. (Tim), Humphries, S.E. (Steve E.), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Iotchkova, V. (Valentina), Isaacs, A. (Aaron), Jackson, D.K. (David K.), Jamshidi, Y. (Yalda), Johnson, J. (Jon), Joyce, C. (Chris), Karczewski, K.J. (Konrad), Kaye, J. (Jane), Keane, T. (Thomas), Kemp, J.P. (John), Kennedy, K. (Karen), Kent, A. (Alastair), Keogh, J. (Julia), Khawaja, F. (Farrah), Kleber, M.E. (Marcus), Van Kogelenberg, M. (Margriet), Kolb-Kokocinski, A. (Anja), Kooner, J.S. (Jaspal S.), Lachance, G. (Genevieve), Langenberg, C. (Claudia), Langford, C. (Cordelia), Lawson, D. (Daniel), Lee, I. (Irene), Leeuwen, E.M. (Elisa) van, Lek, M. (Monkol), Li, R. (Rui), Li, Y. (Yingrui), Liang, J. (Jieqin), Lin, H. (Hong), Liu, R. (Ryan), Lönnqvist, J. (Jouko), Lopes, L.R. (Luis R.), Lopes, M.C. (Margarida), Luan, J., MacArthur, D.G. (Daniel G.), Mangino, M. (Massimo), Marenne, G. (Gaëlle), März, W. (Winfried), Maslen, J. (John), Matchan, A. (Angela), Mathieson, I. (Iain), McGuffin, P. (Peter), McIntosh, A.M. (Andrew), McKechanie, A.G. (Andrew G.), McQuillin, A. (Andrew), Metrustry, S. (Sarah), Migone, N. (Nicola), Mitchison, H.M. (Hannah M.), Moayyeri, A. (Alireza), Morris, J. (James), Morris, R.W. (Richard), Muddyman, D. (Dawn), Muntoni, F., Nordestgaard, B.G. (Børge G.), Northstone, K. (Kate), O'donovan, M.C. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A. (Alexandros), Oualkacha, K. (Karim), Owen, M.J. (Michael J.), Palotie, A. (Aarno), Panoutsopoulou, K. (Kalliope), Parker, V. (Victoria), Parr, J.R. (Jeremy R.), Paternoster, L. (Lavinia), Paunio, T. (Tiina), Payne, F. (Felicity), Payne, S.J. (Stewart J.), Perry, J.R.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V. (Vincent), Pollitt, R.C. (Rebecca C.), Povey, S. (Sue), Quail, M.A. (Michael A.), Quaye, L. (Lydia), Raymond, L. (Lucy), Rehnström, K. (Karola), Ridout, C.K. (Cheryl K.), Ring, S.M. (Susan), Ritchie, G.R.S. (Graham R.S.), Roberts, N. (Nicola), Robinson, R.L. (Rachel L.), Savage, D.B. (David), Scambler, P.J. (Peter), Schiffels, S. (Stephan), Schmidts, M. (Miriam), Schoenmakers, N. (Nadia), Scott, R.H. (Richard H.), Scott, R.A. (Robert), Semple, R.K. (Robert K.), Serra, E. (Eva), Sharp, S.I. (Sally I.), Shaw, A.C. (Adam C.), Shihab, H.A. (Hashem A.), Shin, S.-Y. (So-Youn), Skuse, D. (David), Small, K.S. (Kerrin), Smee, C. (Carol), Smith, A.V. (Davey), Southam, L. (Lorraine), Spasic-Boskovic, O. (Olivera), Spector, T.D. (Timothy), St. Clair, D. (David), St Pourcain, B. (Beate), Stalker, J. (Jim), Stevens, E. (Elizabeth), Sun, J. (Jianping), Surdulescu, G. (Gabriela), Suvisaari, J. (Jaana), Syrris, P. (Petros), Tachmazidou, I. (Ioanna), Taylor, R. (Rohan), Tian, J. (Jing), Tobin, M.D. (Martin), Toniolo, D. (Daniela), Traglia, M. (Michela), Tybjaerg-Hansen, A. (Anne), Valdes, A.M., Vandersteen, A.M. (Anthony M.), Varbo, A. (Anette), Vijayarangakannan, P. (Parthiban), Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, J.T. (James), Wang, G. (Guangbiao), Wang, J. (Jun), Wang, Y. (Yu), Ward, K. (Kirsten), Wheeler, E. (Eleanor), Whincup, P.H. (Peter), Whyte, T. (Tamieka), Williams, H.J. (Hywel J.), Williamson, K.A. (Kathleen), Wilson, C. (Crispian), Wilson, S.G. (Scott), Wong, K. (Kim), Xu, C. (Changjiang), Yang, J. (Jian), Zaza, G. (Gianluigi), Zeggini, E. (Eleftheria), Zhang, F. (Feng), Zhang, P. (Pingbo), and Zhang, W. (Weihua)

Abstract

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this

Published
2015
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23. The UK10K project identifies rare variants in health and disease

Author

Walter, K, Min, JL, Huang, J, Crooks, L, Memari, Y, McCarthy, S, Perry, JRB, Xu, C, Futema, M, Lawson, D, Iotchkova, V, Schiffels, S, Hendricks, AE, Danecek, P, Li, R, Floyd, J, Wain, LV, Barroso, I, Humphries, SE, Hurles, ME, Zeggini, E, Barrett, JC, Plagnol, V, Richards, JB, Greenwood, CMT, Timpson, NJ, Durbin, R, Soranzo, N, Bala, S, Clapham, P, Coates, G, Cox, T, Daly, A, Du, Y, Edkins, S, Ellis, P, Flicek, P, Guo, X, Huang, L, Jackson, DK, Joyce, C, Keane, T, Kolb-Kokocinski, A, Langford, C, Li, Y, Liang, J, Lin, H, Liu, R, Maslen, J, Muddyman, D, Quail, MA, Stalker, J, Sun, J, Tian, J, Wang, G, Wang, J, Wang, Y, Wong, K, Zhang, P, Birney, E, Boustred, C, Chen, L, Clement, G, Cocca, M, Smith, GD, Day, INM, Day-Williams, A, Down, T, Dunham, I, Evans, DM, Gaunt, TR, Geihs, M, Hart, D, Howie, B, Hubbard, T, Hysi, P, Jamshidi, Y, Karczewski, KJ, Kemp, JP, Lachance, G, Lek, M, Lopes, M, MacArthur, DG, Marchini, J, Mangino, M, Mathieson, I, Metrustry, S, Moayyeri, A, Northstone, K, Panoutsopoulou, K, Paternoster, L, Quaye, L, Ring, S, Ritchie, GRS, Shihab, HA, Shin, S-Y, Small, KS, Artigas, MS, Southam, L, Spector, TD, St Pourcain, B, Surdulescu, G, Tachmazidou, I, Tobin, MD, Valdes, AM, Visscher, PM, Ward, K, Wilson, SG, Yang, J, Zhang, F, Zheng, H-F, Anney, R, Ayub, M, Blackwood, D, Bolton, PF, Breen, G, Collier, DA, Craddock, N, Curran, S, Curtis, D, Gallagher, L, Geschwind, D, Gurling, H, Holmans, P, Lee, I, Lonnqvist, J, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Morris, J, O'Donovan, MC, Owen, MJ, Palotie, A, Parr, JR, Paunio, T, Pietilainen, O, Rehnstrom, K, Sharp, SI, Skuse, D, St Clair, D, Suvisaari, J, Walters, JTR, Williams, HJ, Bochukova, E, Bounds, R, Dominiczak, A, Farooqi, IS, Keogh, J, Marenne, GL, Morris, A, O'Rahilly, S, Porteous, DJ, Smith, BH, Wheeler, E, Al Turki, S, Anderson, CA, Antony, D, Beales, P, Bentham, J, Bhattacharya, S, Calissano, M, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Fitzpatrick, DR, Foley, AR, Franklin, CS, Grozeva, D, Mitchison, HM, Muntoni, F, Onoufriadis, A, Parker, V, Payne, F, Raymond, FL, Roberts, N, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, RK, Serra, E, Spasic-Boskovic, O, Stevens, E, van Kogelenberg, M, Vijayarangakannan, P, Williamson, KA, Wilson, C, Whyte, T, Ciampi, A, Oualkacha, K, Bobrow, M, Griffin, H, Kaye, J, Kennedy, K, Kent, A, Smee, C, Charlton, R, Ekong, R, Khawaja, F, Lopes, LR, Migone, N, Payne, SJ, Pollitt, RC, Povey, S, Ridout, CK, Robinson, RL, Scott, RH, Shaw, A, Syrris, P, Taylor, R, Vandersteen, AM, Amuzu, A, Casas, JP, Chambers, JC, Dedoussis, G, Gambaro, G, Gasparini, P, Isaacs, A, Johnson, J, Kleber, ME, Kooner, JS, Langenberg, C, Luan, J, Malerba, G, Maerz, W, Matchan, A, Morris, R, Nordestgaard, BG, Benn, M, Scott, RA, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, van Duijn, CM, van Leeuwen, EM, Varbo, A, Whincup, P, Zaza, G, Zhang, W, Walter, K, Min, JL, Huang, J, Crooks, L, Memari, Y, McCarthy, S, Perry, JRB, Xu, C, Futema, M, Lawson, D, Iotchkova, V, Schiffels, S, Hendricks, AE, Danecek, P, Li, R, Floyd, J, Wain, LV, Barroso, I, Humphries, SE, Hurles, ME, Zeggini, E, Barrett, JC, Plagnol, V, Richards, JB, Greenwood, CMT, Timpson, NJ, Durbin, R, Soranzo, N, Bala, S, Clapham, P, Coates, G, Cox, T, Daly, A, Du, Y, Edkins, S, Ellis, P, Flicek, P, Guo, X, Huang, L, Jackson, DK, Joyce, C, Keane, T, Kolb-Kokocinski, A, Langford, C, Li, Y, Liang, J, Lin, H, Liu, R, Maslen, J, Muddyman, D, Quail, MA, Stalker, J, Sun, J, Tian, J, Wang, G, Wang, J, Wang, Y, Wong, K, Zhang, P, Birney, E, Boustred, C, Chen, L, Clement, G, Cocca, M, Smith, GD, Day, INM, Day-Williams, A, Down, T, Dunham, I, Evans, DM, Gaunt, TR, Geihs, M, Hart, D, Howie, B, Hubbard, T, Hysi, P, Jamshidi, Y, Karczewski, KJ, Kemp, JP, Lachance, G, Lek, M, Lopes, M, MacArthur, DG, Marchini, J, Mangino, M, Mathieson, I, Metrustry, S, Moayyeri, A, Northstone, K, Panoutsopoulou, K, Paternoster, L, Quaye, L, Ring, S, Ritchie, GRS, Shihab, HA, Shin, S-Y, Small, KS, Artigas, MS, Southam, L, Spector, TD, St Pourcain, B, Surdulescu, G, Tachmazidou, I, Tobin, MD, Valdes, AM, Visscher, PM, Ward, K, Wilson, SG, Yang, J, Zhang, F, Zheng, H-F, Anney, R, Ayub, M, Blackwood, D, Bolton, PF, Breen, G, Collier, DA, Craddock, N, Curran, S, Curtis, D, Gallagher, L, Geschwind, D, Gurling, H, Holmans, P, Lee, I, Lonnqvist, J, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Morris, J, O'Donovan, MC, Owen, MJ, Palotie, A, Parr, JR, Paunio, T, Pietilainen, O, Rehnstrom, K, Sharp, SI, Skuse, D, St Clair, D, Suvisaari, J, Walters, JTR, Williams, HJ, Bochukova, E, Bounds, R, Dominiczak, A, Farooqi, IS, Keogh, J, Marenne, GL, Morris, A, O'Rahilly, S, Porteous, DJ, Smith, BH, Wheeler, E, Al Turki, S, Anderson, CA, Antony, D, Beales, P, Bentham, J, Bhattacharya, S, Calissano, M, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Fitzpatrick, DR, Foley, AR, Franklin, CS, Grozeva, D, Mitchison, HM, Muntoni, F, Onoufriadis, A, Parker, V, Payne, F, Raymond, FL, Roberts, N, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, RK, Serra, E, Spasic-Boskovic, O, Stevens, E, van Kogelenberg, M, Vijayarangakannan, P, Williamson, KA, Wilson, C, Whyte, T, Ciampi, A, Oualkacha, K, Bobrow, M, Griffin, H, Kaye, J, Kennedy, K, Kent, A, Smee, C, Charlton, R, Ekong, R, Khawaja, F, Lopes, LR, Migone, N, Payne, SJ, Pollitt, RC, Povey, S, Ridout, CK, Robinson, RL, Scott, RH, Shaw, A, Syrris, P, Taylor, R, Vandersteen, AM, Amuzu, A, Casas, JP, Chambers, JC, Dedoussis, G, Gambaro, G, Gasparini, P, Isaacs, A, Johnson, J, Kleber, ME, Kooner, JS, Langenberg, C, Luan, J, Malerba, G, Maerz, W, Matchan, A, Morris, R, Nordestgaard, BG, Benn, M, Scott, RA, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, van Duijn, CM, van Leeuwen, EM, Varbo, A, Whincup, P, Zaza, G, and Zhang, W

Abstract

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

Published
2015

24. Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel, X-linked syndrome of central hypothyroidism and testicular enlargement

Author

Schoenmakers, N., Sun, Y., Bak, B., Trotsenburg, A.S.P. van, Oostdijk, W., Voshol, P., Cambridge, E., White, J.K., Tissier, P. le, Gharavy, S.N.M., Martinez-Barbera, J.P., Stokvis-Brantsma, W.H., Vulsma, T., Kempers, M.J., Persani, L., Campi, I., Bonomi, M., Beck-Peccoz, P., Zhu, H., Davis, T.M.E., Hokken-Koelega, A.C.S., Blanco, D.G. del, Rangasami, J.J., Ruivenkamp, C.A.L., Laros, J.F.J., Kriek, M., Kant, S.G., Bosch, C.A.J., Biermasz, N.R., Appelman-Dijkstra, N.M., Corssmit, E.P., Hovens, G.C.J., Pereira, A.M., Dunnen, J.T. den, Wade, M.G., Breuning, M.H., Hennekam, R.C., Dattani, M.T., Wit, J.M., Bernard, D.J., Chatterjee, K., and Pediatrics

Published
2013

26. The IGSF1 deficiency syndrome: Characteristics of male and female patients

Author

Joustra, S.D. (Sjoerd), Schoenmakers, N. (Nadia), Persani, L. (Luca), Campi, I. (Irene), Bonomi, E. (Elisa), Radetti, G. (Giorgio), Beck-Peccoz, P. (Paolo), Zhu, H. (H.), Davis, T.M.E. (Timothy M.), Sun, Y. (Yu), Corssmit, E.P. (Eleonora), Appelman-Dijkstra, N.M. (Natasha), Heinen, C.A. (C.), Pereira, A.M. (Alberto), Varewijck, A.J. (Aimee), Janssen, J.A.M.J.L. (Joop), Endert, E. (Erik), Hennekam, R.C.M. (Raoul), Lombardi, M.P. (Paola), Mannens, M.M.A.M. (Marcel), Bak, B. (Beata), Bernard, D.J. (Daniel), Breuning, M.H. (Martijn), Chatterjee, K. (Krishna), Dattani, M.T. (Mehul), Oostdijk, W. (Wilma), Biermasz, N.R., Wit, J.M. (Jan), Trotsenburg, A.S.P. (Paul) van, Joustra, S.D. (Sjoerd), Schoenmakers, N. (Nadia), Persani, L. (Luca), Campi, I. (Irene), Bonomi, E. (Elisa), Radetti, G. (Giorgio), Beck-Peccoz, P. (Paolo), Zhu, H. (H.), Davis, T.M.E. (Timothy M.), Sun, Y. (Yu), Corssmit, E.P. (Eleonora), Appelman-Dijkstra, N.M. (Natasha), Heinen, C.A. (C.), Pereira, A.M. (Alberto), Varewijck, A.J. (Aimee), Janssen, J.A.M.J.L. (Joop), Endert, E. (Erik), Hennekam, R.C.M. (Raoul), Lombardi, M.P. (Paola), Mannens, M.M.A.M. (Marcel), Bak, B. (Beata), Bernard, D.J. (Daniel), Breuning, M.H. (Martijn), Chatterjee, K. (Krishna), Dattani, M.T. (Mehul), Oostdijk, W. (Wilma), Biermasz, N.R., Wit, J.M. (Jan), and Trotsenburg, A.S.P. (Paul) van

Abstract

Context: Ig superfamily member1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. Objective: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.Methods: All patients (n=42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. Results: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone productionwasdelayed, aswerethe growth spurtandpubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. Conclusion: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Published
2013
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28. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

Author

Sun, Y, Bak, B., Schoenmakers, N., van Trotsenburg, A.S., Oostdijk, W., Voshol, P., Cambridge, E., White, J.K., le Tissier, P., Gharavy, S.N., Martinez-Barbera, J.P., Stokvis-Brantsma, W.H., Vulsma, T., Kempers, M.J.E., Persani, L., Campi, I., Bonomi, M., Beck-Peccoz, P., Zhu, H., Davis, T.M., Hokken-Koelega, A.C.S., Del Blanco, D.G., Rangasami, J.J., Ruivenkamp, C.A., Laros, J.F., Kriek, M., Kant, S.G., Bosch, C.A., Biermasz, N.R., Appelman-Dijkstra, N.M., Corssmit, E.P., Hovens, G.C., Pereira, A.M., Dunnen, J.T. den, Wade, M.G., Breuning, M.H., Hennekam, R.C., Chatterjee, K., Dattani, M.T., Wit, J.M., Bernard, D.J., Sun, Y, Bak, B., Schoenmakers, N., van Trotsenburg, A.S., Oostdijk, W., Voshol, P., Cambridge, E., White, J.K., le Tissier, P., Gharavy, S.N., Martinez-Barbera, J.P., Stokvis-Brantsma, W.H., Vulsma, T., Kempers, M.J.E., Persani, L., Campi, I., Bonomi, M., Beck-Peccoz, P., Zhu, H., Davis, T.M., Hokken-Koelega, A.C.S., Del Blanco, D.G., Rangasami, J.J., Ruivenkamp, C.A., Laros, J.F., Kriek, M., Kant, S.G., Bosch, C.A., Biermasz, N.R., Appelman-Dijkstra, N.M., Corssmit, E.P., Hovens, G.C., Pereira, A.M., Dunnen, J.T. den, Wade, M.G., Breuning, M.H., Hennekam, R.C., Chatterjee, K., Dattani, M.T., Wit, J.M., and Bernard, D.J.

Abstract

Item does not contain fulltext, Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

Published
2012

29. Meetresultaten Kunststof GC-elementen: Versie 4

Author

Verhagen, H.J. (author), Van der Hoeven, T. (author), Maaskant, B. (author), Schoenmakers, N. (author), De Gijt, J. (author), Boskma, L. (author), Verhagen, H.J. (author), Van der Hoeven, T. (author), Maaskant, B. (author), Schoenmakers, N. (author), De Gijt, J. (author), and Boskma, L. (author)

Abstract

Anome BV en het Innovatie Test Centrum van Rijkswaterstaat-DWW zijn samen met verschillende partners aan het onderzoeken in hoeverre Ground Consilidators (GC’s) interessant zouden kunnen zijn voor gebruik in Oever- en bodembescherming. De eerste fase van het onderzoek is afgerond en er is besloten om verdergaand onderzoek te doen. In verband met duurzaamheid van het materiaal, is ervoor gekozen om verder onderzoek te verrichten naar GC-elementen van kunststof. Dit onderzoek is gedaan door een drietal studenten van de TU Delft aan de faculteit Civiele Techniek. Voorliggend document bevat de meetresultaten van de kwali- en kwantitatieve experimenten die zijn uitgevoerd om de eigenschappen van kunststoffen GC’s en een pakket GC’s te bepalen.

Published
2006

30. Meetresultaten Kunststof GC-elementen: Project C2: Oever- en Bodembescherming met GC

Author

Verhagen, H.J. (author), Van der Hoeven, T. (author), Maaskant, B. (author), Schoenmakers, N. (author), De Gijt, J. (author), Boskma, L. (author), Verhagen, H.J. (author), Van der Hoeven, T. (author), Maaskant, B. (author), Schoenmakers, N. (author), De Gijt, J. (author), and Boskma, L. (author)

Abstract

Anome BV en het Innovatie Test Centrum van Rijkswaterstaat-DWW zijn samen met verschillende partners aan het onderzoeken in hoeverre Ground Consolidators (GC’s) interessant zouden kunnen zijn voor gebruik in Oever- en bodembescherming. De eerste fase van het onderzoek is afgerond en er is besloten om verdergaand onderzoek te doen. In verband met duurzaamheid van het materiaal, is ervoor gekozen om verder onderzoek te verrichten naar GC-elementen van kunststof. Dit onderzoek is gedaan door een drietal studenten van de TU Delft aan de faculteit Civiele Techniek. Voorliggend document bevat de meetresultaten van de kwali- en kwantitatieve experimenten die zijn uitgevoerd om de eigenschappen van kunststoffen GC’s en een pakket GC’s te bepalen.

Published
2006

34. Over het berekenen van deltaprofielen

Author

Van Malde, J. (author), Schoenmakers, N. (author), Verhage, D.C. (author), Van Malde, J. (author), Schoenmakers, N. (author), and Verhage, D.C. (author)

Abstract

Beschrijving van de rekenmethode voor dijken en dijkprofielen in Zeeland conform de richtlijnen van de Deltacommissie. Berekening van dijkhoogten, bermbreedte, taludhelling.

Published
1972

35. Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism

Author

Aycan, Z, Cangul, H, Muzza, M, Bas, VN, Fugazzola, L, Chatterjee, VK, Persani, L, and Schoenmakers, N

Subjects
Male, Genotype, Infant, Newborn, Genetic Variation, Infant, NADPH Oxidases, Thyroid Function Tests, Dual Oxidases, Severity of Illness Index, 3. Good health, Pedigree, Cohort Studies, Phenotype, Codon, Nonsense, Congenital Hypothyroidism, Humans, Female, Genetic Predisposition to Disease, Retrospective Studies
Abstract

Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the TPO-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic Congenital Hypothyroidism (CH) which may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (eg dietary iodine) and oligogenic modifiers (eg variants in the homologous NADPH-oxidase DUOX1). However, loss of function mutations in DUOX1 have not hitherto been described and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: TSH >100 µU/mL (reference range, RR: 0.5-6.3), P1: Free T4 (FT4) C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43) which segregates with CH in this kindred. Conclusion: This is the first report of digenic mutations in DUOX1 and DUOX2 in association with CH and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a novel digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically-ascertained CH.

36. Intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation

Author

Vasudevan, P, Powell, C, Nicholas, AK, Scudamore, I, Greening, J, Park, S-M, and Schoenmakers, N

Subjects
Pediatric, Clinical, Clinical Medicine and Science, FOS: Biological sciences, Genetics, Reproductive Health and Childbirth, 1114 Paediatrics and Reproductive Medicine, Perinatal Period - Conditions Originating in Perinatal Period, 3. Good health
Abstract

In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases. LEARNING POINTS: CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

37. Semantic prioritization of novel causative genomic variants

Author

Boudellioua, I, Mahamad Razali, RB, Kulmanov, M, Hashish, Y, Bajic, VB, Goncalves-Serra, E, Schoenmakers, N, Gkoutos, GV, Schofield, PN, and Hoehndorf, R

Subjects
retrospective studies, computational biology, phenotype, genetic variation, molecular sequence annotation, algorithms, humans, genome, semantics, exome, 3. Good health
Abstract

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

38. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland

Author

Nicholas, AK, Jaleel, S, Lyons, G, Schoenmakers, E, Dattani, MT, Crowne, E, Bernhard, B, Kirk, J, Roche, EF, Chatterjee, VK, and Schoenmakers, N

Subjects
Male, Heterozygote, Delayed Diagnosis, Homozygote, Infant, Newborn, Sequence Analysis, DNA, Thyrotropin, beta Subunit, United Kingdom, 3. Good health, Pedigree, Neonatal Screening, Hypothyroidism, Congenital Hypothyroidism, Humans, Female, Ireland
Abstract

OBJECTIVE: Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH-based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. DESIGN, PATIENTS AND MEASUREMENTS: Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). RESULTS: Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4-kB TSHB deletion (kindred 2, c.1-4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. CONCLUSIONS: This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine-binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.

39. The Clinical and Molecular Characterization of Patients With Dyshormonogenic Congenital Hypothyroidism Reveals Specific Diagnostic Clues for DUOX2 Defects

Author

Maria Antonia Maffini, Valentina Cirello, I. Zamproni, Giovanna Weber, Marina Muzza, Laura Fugazzola, F. Gallo, Paolo Beck-Peccoz, K. Maruca, Luciano Beccaria, Soo-Mi Park, Luca Persani, Nadia Schoenmakers, Maria Cristina Vigone, Sarah Rabbiosi, Muzza, M, Rabbiosi, S, Vigone, Mc, Zamproni, I, Cirello, V, Maffini, Ma, Maruca, K, Schoenmakers, N, Beccaria, L, Gallo, F, Park, Sm, Beck Peccoz, P, Persani, L, Weber, Giovanna, and Fugazzola, L.

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, DNA Mutational Analysis, Clinical Biochemistry, Mutation, Missense, Context (language use), medicine.disease_cause, Polymorphism, Single Nucleotide, Biochemistry, Frameshift mutation, Exon, Endocrinology, Thyroid dyshormonogenesis, Gene Frequency, Internal medicine, Congenital Hypothyroidism, Humans, Medicine, Missense mutation, Child, Genetic Association Studies, Mutation, business.industry, Biochemistry (medical), Infant, NADPH Oxidases, medicine.disease, Dual Oxidases, Exon skipping, Congenital hypothyroidism, Child, Preschool, business, HeLa Cells
Abstract

CONTEXT: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. OBJECTIVE: This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). PATIENTS AND METHODS: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. RESULTS: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. CONCLUSIONS: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.

Published
2014

40. Mitochondrial Oxidative Phosphorylation Is Impaired in Patients with Congenital Lipodystrophy

Author

T. Adrian Carpenter, Alessandra Gambineri, David B. Savage, V. Irene Campi, Peter R. Murgatroyd, Graham J. Kemp, Anna Stears, Stephen O'Rahilly, Alison Sleigh, Nadia Schoenmakers, Kerrie Thackray, Sath Nag, Laura Watson, Soren Brage, Sleigh A, Stears A, Thackray K, Watson L, Gambineri A, Nag S, Campi VI, Schoenmakers N, Brage S, Carpenter TA, Murgatroyd PR, O'Rahilly S, Kemp GJ, and Savage DB

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Phosphocreatine, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, INSULIN-RESISTANCE, SKELETAL-MUSCLE, DYSFUNCTION, EXERCISE, PATHOGENESIS, METABOLISM, STRESS, 030209 endocrinology & metabolism, White adipose tissue, Oxidative phosphorylation, Type 2 diabetes, Biology, Biochemistry, Oxidative Phosphorylation, Quadriceps Muscle, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Insulin resistance, Lipodystrophy, Congenital Generalized, Congenital lipodystrophy, Internal medicine, medicine, Humans, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Biochemistry (medical), Skeletal muscle, JCEM Online: Brief Reports, medicine.disease, Mitochondria, Muscle, medicine.anatomical_structure, chemistry, Female, Insulin Resistance, Body mass index
Abstract

Objective: Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle. Research Design and Methods: Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using P-31-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls. Results: The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P < 0.001). This substantial (similar to 35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates. Conclusions: Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.

Published
2012

41. SMIM1 absence is associated with reduced energy expenditure and excess weight.

Author

Stefanucci L, Moslemi C, Tomé AR, Virtue S, Bidault G, Gleadall NS, Watson LPE, Kwa JE, Burden F, Farrow S, Chen J, Võsa U, Burling K, Walker L, Ord J, Barker P, Warner J, Frary A, Renhstrom K, Ashford SE, Piper J, Biggs G, Erber WN, Hoffman GJ, Schoenmakers N, Erikstrup C, Rieneck K, Dziegiel MH, Ullum H, Azzu V, Vacca M, Aparicio HJ, Hui Q, Cho K, Sun YV, Wilson PW, Bayraktar OA, Vidal-Puig A, Ostrowski SR, Astle WJ, Olsson ML, Storry JR, Pedersen OB, Ouwehand WH, Chatterjee K, Vuckovic D, and Frontini M

Subjects
Adult, Female, Humans, Male, Middle Aged, Adiponectin genetics, Adiponectin metabolism, Case-Control Studies, Loss of Function Mutation, Membrane Proteins genetics, Overweight genetics, Thyroid Hormones blood, Thyroid Hormones metabolism, Energy Metabolism genetics, Leptin blood, Leptin genetics, Leptin metabolism, Obesity genetics, Obesity metabolism
Abstract

Background: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments., Methods: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1 -/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan., Findings: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure., Conclusion: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them., Funding: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant., Competing Interests: Declaration of interests J.S. is the deputy CEO and 50% owner of BLUsang AB. He holds patents on Vel genotyping (inventors: Jill Storry, Magnus Jöud, Björn Nilsson, and Martin L. Olsson). J.S. has received speaker fees, royalties, and honoraria from the following companies: Grifols Diagnostic Solutions, QuidelOrtho Inc., and Biorad Laboratories. J.S. receives an honorarium for Section Editor work, Vox Sanguinis from John Wiley & Sons Ltd. J.S. is Vice President of the International Society of Blood Transfusion and married to Professor M.L.O. M.L.O. is CEO and 50% owner of BLUsang AB. M.L.O. holds patents on Vel genotyping (inventors: Jill Storry, Magnus Jöud, Björn Nilsson, and Martin L. Olsson). M.L.O. received speaker fees, royalties, and honoraria from the following companies: Grifols Diagnostic Solutions, QuidelOrtho Inc., and Biorad Laboratories. M.L.O. is married to Adjunct Professor J.S. W.N.E. is chair of the International Council for Standardization in Haematology. W.N.E. works as advisor for Scorpio Labs and is on the editorial board of the Journal of Clinical Pathology. W.H.O. is chair of the Blood Transfusion Genomics Consortium. W.H.O. is in receipt of an educational/research grant from Thermo Fisher Scientific. N.G. offers scientific consulting services to Thermo Fisher Scientific., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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42. Approach to the Patient With Raised Thyroid Hormones and Nonsuppressed TSH.

Author

Moran C, Schoenmakers N, Halsall D, Oddy S, Lyons G, van den Berg S, Gurnell M, and Chatterjee K

Subjects
Humans, Thyroid Hormones, Thyrotropin metabolism, Thyroid Function Tests, Thyroxine therapeutic use, Triiodothyronine
Abstract

Measurement of free thyroid hormones (THs) and thyrotropin (TSH) using automated immunoassays is central to the diagnosis of thyroid dysfunction. Using illustrative cases, we describe a diagnostic approach to discordant thyroid function tests, focusing on entities causing elevated free thyroxine and/or free triiodothyronine measurements with nonsuppressed TSH levels. Different types of analytical interference (eg, abnormal thyroid hormone binding proteins, antibodies to iodothyronines or TSH, heterophile antibodies, biotin) or disorders (eg, resistance to thyroid hormone β or α, monocarboxylate transporter 8 or selenoprotein deficiency, TSH-secreting pituitary tumor) that can cause this biochemical pattern will be considered. We show that a structured approach, combining clinical assessment with additional laboratory investigations to exclude assay artifact, followed by genetic testing or specialized imaging, can establish a correct diagnosis, potentially preventing unnecessary investigation or inappropriate therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Published
2024
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43. Congenital Central Hypothyroidism Caused by Novel Variants in IGSF1 Gene : Case Series of three patients.

Author

MacGloin H, Schoenmakers N, Moorwood C, Buchanan CR, and Arya VB

Abstract

Introduction: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Loss of function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene causes X-linked central hypothyroidism and represent the most common genetic cause of central hypothyroidism. In addition to central hypothyroidism, some patients with IGSF1 deficiency have hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Here, we describe a case-series of three patients with central hypothyroidism caused by two novel IGSF1mutations., Case Presentation: Three males (including two siblings) were diagnosed with central hypothyroidism between 0.06 - 1.5 years of age. Additional features included hypoprolactinemia, normal cortisol and growth hormone - insulin like growth factor 1 axis, high body mass index, birth weight greater than 0 SDS and isolated speech delay. Genetic testing identified two novel IGSF1 mutations [(c.1829G>A, p.W610* and c.3692G>A, p.(Cys123Tyr)]. Both variants have not been reported in the gnoMAD database (~90,000 individuals) and are predicted deleterious., Conclusions: Loss of function mutations in IGSF1 represent the most common genetic cause of central hypothyroidism Detailed phenotyping of IGSF1 deficiency from extensive case series have led to formulation of recommendations for clinical management of these patients. We have highlighted the potential adverse consequences of delayed treatment of CCH (speech delay)., (S. Karger AG, Basel.)

Published
2024
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44. Rare case of central congenital hypothyroidism due to a TSHβ mutation presenting with macro-orchidism.

Author

Karguppikar MB, Schoenmakers N, Khadilkar V, and Khadilkar A

Subjects
Infant, Child, Male, Humans, Thyroxine therapeutic use, Thyrotropin, Mutation, Thyroid Function Tests, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism drug therapy, Congenital Hypothyroidism genetics
Abstract

A male infant was brought to our paediatric endocrine unit with typical clinical features of congenital hypothyroidism (CH) and striking macro-orchidism. On evaluation, free T3, free T4 and thyroid stimulating hormone (TSH) were found to be low, suggestive of congenital CH. Cortisol was within reference range and prolactin was mildly elevated. No suspicious lesions were encountered on neurosonography. On commencing treatment with thyroxine, clinical features of hypothyroidism showed dramatic improvement with regression of testicular enlargement. Genetic analysis revealed deletion of the TSHβ gene.Our case highlights a rare presentation of central CH with macro-orchidism in a genetically proven deletion of TSHβ gene. Macro-orchidism has been widely reported in IGSF-1 mutations leading to central CH; however, central CH and macro-orchidism have not been reported in association with TSHβ deletions., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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45. Genetic disorders of thyroid development, hormone biosynthesis and signalling.

Author

Moran C, Schoenmakers N, Visser WE, Schoenmakers E, Agostini M, and Chatterjee K

Subjects
Humans, Iodide Peroxidase genetics, Signal Transduction genetics, Transcription Factors, Hypothyroidism genetics, Thyroid Hormones metabolism
Abstract

Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Published
2022
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46. MECHANISMS IN ENDOCRINOLOGY: The pathophysiology of transient congenital hypothyroidism.

Author

Peters C and Schoenmakers N

Subjects
Dual Oxidases genetics, Humans, Infant, Newborn, Congenital Hypothyroidism diagnosis, Infant, Newborn, Diseases, Iodine
Abstract

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Published
2022
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47. A Novel Mutation in the Thyroglobulin Gene Resulting in Neonatal Goiter and Congenital Hypothyroidism in an Eritrean Infant

Author

Stern E, Schoenmakers N, Nicholas AK, Kassif E, Hamiel OP, and Yeshayahu Y

Subjects
Eritrea, Female, Humans, Mutation, Nucleotides, Thyroglobulin genetics, Congenital Hypothyroidism genetics, Fetal Diseases, Goiter genetics
Abstract

Congenital hypothyroidism (CH) due to dyshormonogenesis may occur due to mutations in any of the key genes involved in thyroid hormone biosynthesis ( TG, TPO, DUOX2, DUOXA2, SLC5A5, IYD, SLC26A4 and SLC26A7 ). Mutations in the thyroglobulin gene ( TG ) are frequently associated with goiter, which may present fetally or neonatally, although a spectrum of phenotypes is reported. We present the case of a woman of Eritrean origin who presented in the third trimester of pregnancy in the early stages of labor. Ultrasound at presentation revealed a fetal neck swelling consistent with a goiter. Following delivery by Caesarian section with minimal respiratory support, the infant was found to be hypothyroid with undetectable serum levels of thyroglobulin. Sequencing of the TG revealed a homozygous donor splice site pathogenic variant (c.5686+1delG) not previously described in the literature. Levothyroxine treatment resulted in normal growth and psychomotor development. Goitrous CH with inappropriately low thyroglobulin has previously been reported in patients harbouring homozygous single nucleotide substitutions at the same TG donor splice site, which result in exon skipping and retention of malformed thyroglobulin by the endoplasmic reticulum. We conclude that the TG c.5686+1delG pathogenic variant is the likely basis for our patient’s fetal goiter and CH, and that the clinical phenotype associated with TG c.5686+1delG is comparable to that seen with single nucleotide substitutions at the same site.

Published
2022
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48. An Approach to a Patient With Primary Hyperparathyroidism and a Suspected Ectopic Parathyroid Adenoma.

Author

Glasgow C, Lau EYC, Aloj L, Harper I, Cheow H, Das T, Berman L, Powlson AS, Bashari WA, Challis BG, Marker A, Moyle P, Mohamed IA, Schoenmakers N, Broomfield J, Oddy S, Moran C, Gurnell M, Jani P, Masterson L, Fish B, and Casey RT

Subjects
Adult, Female, Humans, Parathyroid Glands surgery, Parathyroid Hormone, Parathyroidectomy adverse effects, Adenoma complications, Adenoma diagnosis, Adenoma surgery, Hyperparathyroidism, Primary complications, Hyperparathyroidism, Primary diagnosis, Parathyroid Neoplasms complications, Parathyroid Neoplasms diagnosis, Parathyroid Neoplasms surgery
Abstract

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia driven by excess parathyroid hormone (PTH) secretion. PHPT is a common endocrine condition with a prevalence of 1 to 7 cases per 1000 adults. PHPT typically presents in the fifth or sixth decade and shows significant female preponderance. Solitary hyperfunctioning parathyroid adenomas account for 85% to 90% of PHPT cases. The remaining 10% to 15% include cases of multiglandular disease (multiple adenomas or hyperplasia) and, rarely, parathyroid carcinoma (1%). Ectopic parathyroid adenomas may arise due to abnormal embryological migration of the parathyroid glands and can be difficult to localize preoperatively, making surgical cure challenging on the first attempt. The potential existence of multiglandular disease should be considered in all patients in whom preoperative localization fails to identify a target adenoma or following unsuccessful parathyroidectomy. Risk factors for multiglandular disease include underlying genetic syndromes (eg, MEN1/2A), lithium therapy, or previous radiotherapy. In addition to multifocal disease, the possibility of an ectopic parathyroid gland should also be considered in patients requiring repeat parathyroid surgery. In this article, we use illustrative clinical vignettes to discuss the approach to a patient with primary hyperparathyroidism (PHPT) and a suspected ectopic parathyroid adenoma., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2022
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49. Establishing risk factors and outcomes for congenital hypothyroidism with gland in situ using population-based data linkage methods: study protocol.

Author

Ruiz Nishiki M, Cabecinha M, Knowles R, Peters C, Aitkenhead H, Ifederu A, Schoenmakers N, Sebire NJ, Walker E, and Hardelid P

Subjects
Child, Cohort Studies, Follow-Up Studies, Humans, Infant, Newborn, Information Storage and Retrieval, Risk Factors, Congenital Hypothyroidism diagnosis
Abstract

Introduction: There has been an increase in the birth prevalence of congenital hypothyroidism (CH) since the introduction of newborn screening, both globally and in the UK. This increase can be accounted for by an increase in CH with gland in situ (CH-GIS). It is not known why CH-GIS is becoming more common, nor how it affects the health, development and learning of children over the long term. Our study will use linked administrative health, education and clinical data to determine risk factors for CH-GIS and describe long-term health and education outcomes for affected children., Methods and Analysis: We will construct a birth cohort study based on linked, administrative data to determine what factors have contributed to the increase in the birth prevalence of CH-GIS in the UK. We will also set up a follow-up study of cases and controls to determine the health and education outcomes of children with and without CH-GIS. We will use logistic/multinomial regression models to establish risk factors for CH-GIS. Changes in the prevalence of risk factors over time will help to explain the increase in birth prevalence of CH-GIS. Multivariable generalised linear models or Cox proportional hazards regression models will be used to assess the association between type of CH and school performance or health outcomes., Ethics and Dissemination: This study has been approved by the London Queen Square Research Ethics Committee and the Health Research Authority's Confidentiality Advisory Group CAG. Approvals are also being sought from each data provider. Obtaining approvals from CAG, data providers and information governance bodies have caused considerable delays to the project. Our methods and findings will be published in peer-reviewed journals and presented at academic conferences., Competing Interests: Competing interests: RK holds an honorary clinical consultant contract with the ANNB screening programme, now hosted by NHS England and Improvement (formally with Public Health England). RK is also the chair of the ANNB Research Advisory Committee. MRN holds an honorary contract with NHS Digital. No other authors have any competing interests to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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50. Brief Report: A Novel Sodium/Iodide Symporter Mutation, S356F, Causing Congenital Hypothyroidism.

Author

Durgia H, Nicholas AK, Schoenmakers E, Dickens JA, Halanaik D, Sahoo J, Kamalanathan S, and Schoenmakers N

Subjects
Female, Humans, India, Infant, Newborn, Congenital Hypothyroidism genetics, Mutation genetics, Symporters genetics
Abstract

The sodium-iodide symporter (NIS, SLC5A5) is expressed at the basolateral membrane of the thyroid follicular cell, and facilitates the thyroidal iodide uptake required for thyroid hormone biosynthesis. Biallelic loss-of-function mutations in NIS are a rare cause of dyshormonogenic congenital hypothyroidism. Affected individuals typically exhibit a normally sited, often goitrous thyroid gland, with absent uptake of radioiodine in the thyroid and other NIS-expressing tissues. We report a novel homozygous NIS mutation (c.1067 C>T, p.S356F) in four siblings from a consanguineous Indian kindred, presenting with significant hypothyroidism. Functional characterization of the mutant protein demonstrated impaired plasma membrane localization and cellular iodide transport.

Published
2022
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