Dataset Information

High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism.

ABSTRACT: OBJECTIVE:Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients' inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants. DESIGN:243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study. METHODS:A custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS:In total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in 'thyroid dysgenesis' (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in 'dyshormonogenesis' (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic. CONCLUSIONS:In contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.

SUBMITTER: Makretskaya N

PROVIDER: S-EPMC6150524 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism.

Makretskaya Nina N Bezlepkina Olga O Kolodkina Anna A Kiyaev Alexey A Vasilyev Evgeny V EV Petrov Vasily V Kalinenkova Svetlana S Malievsky Oleg O Dedov Ivan I II Tiulpakov Anatoly A

PloS one 20180921 9

<h4>Objective</h4>Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients' inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants.<h4>Design</h4>243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 ...[more]

PMID: 30240412

Similar Datasets

Project description:BackgroundAn association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation.MethodsAudiometry was undertaken prospectively in 66 patients aged 3-21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies.ResultsHI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT4) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT4 levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 μg/dL, p = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies.ConclusionsOur findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT4 therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.

Dataset Information

High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism.

Publications

High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets