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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.

MODY1 and MODY3 represent rare causes of diabetes in pregnancy. Establishing a molecular diagnosis of MODY1 or MODY3 during pregnancy may be important for minimizing risk of perinatal complications and for improving glycemic control after pregnancy. The objective of the study was to evaluate the contribution of mutations in HNF4A and HNF1A genes in development of diabetes in pregnancy and to describe clinical characteristics of diabetes in pregnancy associated with these mutations. 230 pregnant women (20-43 years) with different type of glucose intolerance complicated during their current pregnancy were included in the study. A custom NGS panel targeting 28 diabetes causative genes was used for sequencing. Heterozygous mutations in HNF4A and HNF1A genes were detected in 3% of cases. Mutations p.I271T in HNF4A gene and p.L148F, p.Y265C, p.G288W in HNF1A gene were novel. This study includes a description of patients with pregnancy diabetes due to mutations in hepatocyte nuclear factors.

The diagnosis of MODY as a subtype of gestational diabetes mellitus (GDM) is important for an adequate management during pregnancy and the postnatal period. The present report describes a case of GDM caused by a synonymous с.666C>G р.V222V substitution in the GCK gene. The variant, which was initially ranked as ‘likely benign’, was later proven to be pathogenic by in vitro studies. The с.666C>G substitution led to the use of a new donor splice site and synthesis of the aberrant mRNA with deletion of 16 base pairs. The case illustrates that additional clinical and experimental data may be required for the correct interpretation of sequence variants pathogenicity.

An erratum on «A synonymous variant in GCK gene as a cause of gestational diabetes mellitus» by Natalya A. Zubkova, Petr M. Rubtsov, Liudmila I. Ibragimova, Nina A. Makretskaya, Evgeny V. Vasiliev, Vasily M. Petrov, Anatoly N. Tiulpakov (2019). Diabetes mellitus. 22(2). doi: 10.14341/DM9938An error was made in the list of authors: Fatima F. Burumkulova was not indicated as author of this article. The correct list of authors: Natalya A. Zubkova, Petr M. Rubtsov, Fatima F. Burumkulova, Liudmila I. Ibragimova, Nina A. Makretskaya, Evgeny V. Vasiliev, Vasily M. Petrov, Anatoly N. Tiulpakov.The editorial board apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.