Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Adeline K Nicholas; Eva G Serra; Hakan Cangul; Saif Alyaarubi; Irfan Ullah; Erik Schoenmakers; Asma Deeb; Abdelhadi M Habeb; Mohammad Almaghamsi; Catherine Peters; Nisha Nathwani; Zehra Aycan; Halil Saglam; Ece Bober; Mehul Dattani; Savitha Shenoy; Philip G Murray; Amir Babiker; Ruben Willemsen; Ajay Thankamony; Greta Lyons; Rachael Irwin; Raja Padidela; Kavitha Tharian; Justin H Davies; Vijith Puthi; Soo-Mi Park; Ahmed F Massoud; John W Gregory; Assunta Albanese; Evelien Pease-Gevers; Howard Martin; Kim Brugger; Eamonn R Maher; V Krishna K Chatterjee; Carl A Anderson; Nadia Schoenmakers

doi:10.1210/jc.2016-1879

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Adeline K Nicholas, Eva G Serra, Hakan Cangul, Saif Alyaarubi, Irfan Ullah, Erik Schoenmakers, Asma Deeb, Abdelhadi M Habeb, Mohammad Almaghamsi, Catherine Peters, Nisha Nathwani, Zehra Aycan, Halil Saglam, Ece Bober, Mehul Dattani, Savitha Shenoy, Philip G Murray, Amir Babiker, Ruben Willemsen, Ajay ThankamonyGreta Lyons, Rachael Irwin, Raja Padidela, Kavitha Tharian, Justin H Davies, Vijith Puthi, Soo-Mi Park, Ahmed F Massoud, John W Gregory, Assunta Albanese, Evelien Pease-Gevers, Howard Martin, Kim Brugger, Eamonn R Maher, V Krishna K Chatterjee, Carl A Anderson, Nadia Schoenmakers

Division of Developmental Biology & Medicine (L5)

Uludag University

Research output: Contribution to journal › Article › peer-review

59 Downloads (Pure)

Abstract

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.

OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.

PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.

RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.

CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

Original language	English
Pages (from-to)	4521-4531
Number of pages	11
Journal	The Journal of Clinical Endocrinology and Metabolism
Volume	101
Issue number	12
Early online date	15 Aug 2016
DOIs	https://doi.org/10.1210/jc.2016-1879
Publication status	Published - Dec 2016

Keywords

Autoantigens/genetics
Congenital Hypothyroidism/genetics
Humans
Iodide Peroxidase/genetics
Iron-Binding Proteins/genetics
Mutation
Pedigree
Phenotype
Receptors, Thyrotropin/genetics
Thyroglobulin/genetics

Access to Document

10.1210/jc.2016-1879Licence: CC BY

jcem4521Final published version, 2.2 MBLicence: CC BY

Cite this

Nicholas, A. K., Serra, E. G., Cangul, H., Alyaarubi, S., Ullah, I., Schoenmakers, E., Deeb, A., Habeb, A. M., Almaghamsi, M., Peters, C., Nathwani, N., Aycan, Z., Saglam, H., Bober, E., Dattani, M., Shenoy, S., Murray, P. G., Babiker, A., Willemsen, R., ... Schoenmakers, N. (2016). Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ. The Journal of Clinical Endocrinology and Metabolism, 101(12), 4521-4531. https://doi.org/10.1210/jc.2016-1879

@article{9586acc6ea6a416fa8565c9637afdc1f,

title = "Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ",

abstract = "CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.",

keywords = "Autoantigens/genetics, Congenital Hypothyroidism/genetics, Humans, Iodide Peroxidase/genetics, Iron-Binding Proteins/genetics, Mutation, Pedigree, Phenotype, Receptors, Thyrotropin/genetics, Thyroglobulin/genetics",

author = "Nicholas, {Adeline K} and Serra, {Eva G} and Hakan Cangul and Saif Alyaarubi and Irfan Ullah and Erik Schoenmakers and Asma Deeb and Habeb, {Abdelhadi M} and Mohammad Almaghamsi and Catherine Peters and Nisha Nathwani and Zehra Aycan and Halil Saglam and Ece Bober and Mehul Dattani and Savitha Shenoy and Murray, {Philip G} and Amir Babiker and Ruben Willemsen and Ajay Thankamony and Greta Lyons and Rachael Irwin and Raja Padidela and Kavitha Tharian and Davies, {Justin H} and Vijith Puthi and Soo-Mi Park and Massoud, {Ahmed F} and Gregory, {John W} and Assunta Albanese and Evelien Pease-Gevers and Howard Martin and Kim Brugger and Maher, {Eamonn R} and Chatterjee, {V Krishna K} and Anderson, {Carl A} and Nadia Schoenmakers",

year = "2016",

month = dec,

doi = "10.1210/jc.2016-1879",

language = "English",

volume = "101",

pages = "4521--4531",

journal = "The Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "12",

}

Nicholas, AK, Serra, EG, Cangul, H, Alyaarubi, S, Ullah, I, Schoenmakers, E, Deeb, A, Habeb, AM, Almaghamsi, M, Peters, C, Nathwani, N, Aycan, Z, Saglam, H, Bober, E, Dattani, M, Shenoy, S, Murray, PG, Babiker, A, Willemsen, R, Thankamony, A, Lyons, G, Irwin, R, Padidela, R, Tharian, K, Davies, JH, Puthi, V, Park, S-M, Massoud, AF, Gregory, JW, Albanese, A, Pease-Gevers, E, Martin, H, Brugger, K, Maher, ER, Chatterjee, VKK, Anderson, CA & Schoenmakers, N 2016, 'Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ', The Journal of Clinical Endocrinology and Metabolism, vol. 101, no. 12, pp. 4521-4531. https://doi.org/10.1210/jc.2016-1879

TY - JOUR

T1 - Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

AU - Nicholas, Adeline K

AU - Serra, Eva G

AU - Cangul, Hakan

AU - Alyaarubi, Saif

AU - Ullah, Irfan

AU - Schoenmakers, Erik

AU - Deeb, Asma

AU - Habeb, Abdelhadi M

AU - Almaghamsi, Mohammad

AU - Peters, Catherine

AU - Nathwani, Nisha

AU - Aycan, Zehra

AU - Saglam, Halil

AU - Bober, Ece

AU - Dattani, Mehul

AU - Shenoy, Savitha

AU - Murray, Philip G

AU - Babiker, Amir

AU - Willemsen, Ruben

AU - Thankamony, Ajay

AU - Lyons, Greta

AU - Irwin, Rachael

AU - Padidela, Raja

AU - Tharian, Kavitha

AU - Davies, Justin H

AU - Puthi, Vijith

AU - Park, Soo-Mi

AU - Massoud, Ahmed F

AU - Gregory, John W

AU - Albanese, Assunta

AU - Pease-Gevers, Evelien

AU - Martin, Howard

AU - Brugger, Kim

AU - Maher, Eamonn R

AU - Chatterjee, V Krishna K

AU - Anderson, Carl A

AU - Schoenmakers, Nadia

PY - 2016/12

Y1 - 2016/12

N2 - CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

AB - CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

KW - Autoantigens/genetics

KW - Congenital Hypothyroidism/genetics

KW - Humans

KW - Iodide Peroxidase/genetics

KW - Iron-Binding Proteins/genetics

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - Receptors, Thyrotropin/genetics

KW - Thyroglobulin/genetics

U2 - 10.1210/jc.2016-1879

DO - 10.1210/jc.2016-1879

M3 - Article

C2 - 27525530

SN - 0021-972X

VL - 101

SP - 4521

EP - 4531

JO - The Journal of Clinical Endocrinology and Metabolism

JF - The Journal of Clinical Endocrinology and Metabolism

IS - 12

ER -

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Abstract

Keywords

Access to Document

Fingerprint

Cite this