New genetics in congenital hypothyroidism

Stoupa, Athanasia; Kariyawasam, Dulanjalee; Muzza, Marina; Filippis, Tiziana de; Fugazzola, Laura; Polak, Michel; Persani, Luca; Carré, Aurore

doi:10.1007/s12020-021-02646-9

Cited by 40 publications

(53 citation statements)

References 47 publications

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“…An oligogenic model of inheritance for CH has also been proposed by previous studies, possibly together with a modulation by environmental modifiers [5,22]. This may also apply to our patients, at least to the patient, where exon sequencing has been performed.…”

Section: Discussionsupporting

confidence: 75%

Identification of ZBTB26 as a Novel Risk Factor for Congenital Hypothyroidism

Vick

Eberle

Choukair

et al. 2021

Genes

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Congenital primary hypothyroidism (CH; OMIM 218700) is characterized by an impaired thyroid development, or dyshormonogenesis, and can lead to intellectual disability and growth retardation if untreated. Most of the children with congenital hypothyroidism present thyroid dysgenesis, a developmental anomaly of the thyroid. Various genes have been associated with thyroid dysgenesis, but all known genes together can only explain a small number of cases. To identify novel genetic causes for congenital hypothyroidism, we performed trio whole-exome sequencing in an affected newborn and his unaffected parents. A predicted damaging de novo missense mutation was identified in the ZBTB26 gene (Zinc Finger A and BTB Domain containing 26). An additional cohort screening of 156 individuals with congenital thyroid dysgenesis identified two additional ZBTB26 gene variants of unknown significance. To study the underlying disease mechanism, morpholino knock-down of zbtb26 in Xenopus laevis was carried out, which demonstrated significantly smaller thyroid anlagen in knock-down animals at tadpole stage. Marker genes expressed in thyroid tissue precursors also indicated a specific reduction in the Xenopus ortholog of human Paired-Box-Protein PAX8, a transcription factor required for thyroid development, which could be rescued by adding zbtb26. Pathway and network analysis indicated network links of ZBTB26 to PAX8 and other genes involved in thyroid genesis and function. GWAS associations of ZBTB26 were found with height. Together, our study added a novel genetic risk factor to the list of genes underlying congenital primary hypothyroidism and provides additional support that de novo mutations, together with inherited variants, might contribute to the genetic susceptibility to CH.

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Section: Discussionsupporting

confidence: 75%

Identification of ZBTB26 as a Novel Risk Factor for Congenital Hypothyroidism

Vick

Eberle

Choukair

et al. 2021

Genes

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“…The synthesis, secretion, and action of thyroid hormones are regulated by various genes (11). The genes reported to affect thyroid hormone synthesis and secretion dysfunction comprise of DUOX2, DUOXA2, IYD, SLC5A5, TG, TPO, SLC26A4, and SECISBP2 (12)(13)(14)(15); genes that control the biosynthetic pathway of thyroid stimulating hormone include TSH, THRB, TRHR, and IGSF1 (16); pituitary development-related genes POU1F1, PROP1, and HESX1, and genes that can cause diverse syndromes and abnormal thyroid function, including GLIS3, GNAS, KDM6A, KMT2D, NKX2-1, NKX2-5, and UBR1 (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Mutation Spectra of 28 Pathogenic Genes Associated With Congenital Hypothyroidism in the Chinese Han Population

Hao

Dong

et al. 2021

Front. Endocrinol.

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PurposeCongenital hypothyroidism (CH) is the most common neonatal endocrine disease; its early detection ensures successful treatment and prevents complications. However, its molecular etiology remains unclear.MethodsWe used second-generation sequencing to detect 28 pathogenic genes in 15 Chinese Han patients with CH in Shenzhen, China, and analyzed the genetic pattern of the pathogenic genes through their pedigrees. The pathogenicity assessment of gene mutations was performed based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines, inheritance models, and published evidence.ResultsMutations in several target genes were identified in 14 of 15 patients (93.33%); these mutations were distributed in eight genes (DUOX2, DUOXA2, TPO, TG, TSHR, FOXE1, KDM6A, and POU1F1). DUOX2 exhibited the highest mutation frequency (44%, 11/25), followed by TPO (16%, 4/25) and TG (16%, 4/25). DUOX2 exhibited the highest biallelic mutation (7/15). Eight out of 25 variants verified by the ACMG guidelines were classified as pathogenic (P, category 1) or possibly pathogenic (LP, Type 2), namely six variants of DUOX2, and one variant of TPO and DUOXA2. Five new mutations were detected: one in DUOX2, which was located in the splicing region of mRNA (c.1575-1G>A), three new missense mutants, p.A291T, p.R169W, and p. S1237dup, and one new TPO missense variant c.2012G>T (p.W671L). The main criteria for determining the genotype–phenotype relationship were a diagnostic detection rate of 53.33% (8/15) and combination of three or more gene mutations.ConclusionsCH gene mutations in the population may be mainly manifested in genes influencing thyroid hormone synthesis, such as DUOX2 compound heterozygous mutations, which exhibited a high detection rate. The clinical manifestations are diverse, and mainly include transient CH. Therefore, genetic screening is recommended for CH patients to determine the correlation between clinical phenotypes and gene mutations, which will assist in clinical management.

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“…TD, which is caused by abnormal development of the thyroid gland, has been reported to be associated with mutations in the following genes: thyroidstimulating hormone receptor (TSHR), NK2 homeobox 1 (NKX2-1), NK2 homeobox 5 (NKX2-5), forkhead box E1 (FOXE1), paired box 8 (PAX8), and GLIS family zinc finger 3 (GLIS3) (3). DH has been associated with mutations in genes encoding known components of the thyroid hormone biosynthesis machinery (4), such as dual oxidase 2 (DUOX2), dual-oxidase maturation factor 2 (DUOXA2), thyroglobulin (TG), thyroid peroxidase (TPO), solute carrier family 5 member 5 (SLC5A5), solute carrier family 26 member 4 (SLC26A4), and iodotyrosine deiodinase (IYD) (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…To date, more than 20 genes have been reported to be involved in the pathogenesis of primary CH (2), and new genetic defects continue to be identified due to the use of efficient genetic approaches, such as target region sequencing and whole-exome sequencing (WES) (6). However, these reported genes cannot fully explain the molecular etiology of CH.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort

et al. 2021

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BackgroundThe molecular etiology and the genotype–phenotype correlation of congenital hypothyroidism (CH) remain unclear.MethodsWe performed genetic analysis in 42 newborns with CH using whole-exome sequencing. Patients were divided into a single-gene group and a multi-gene group according to the number of affected genes, or divided into a monoallelic group, a biallelic group, and an oligogenic group according to the pattern of the detected variants. The clinical characteristics were compared between groups.ResultsThyroid dysgenesis (TD) was observed in 10 patients and goiter in 5 patients, whereas 27 patients had normal-sized gland-in-situ (GIS). We identified 58 variants in five genes in 29 patients. The genes with the most frequent variants were DUOX2 (70.7%), followed by TSHR (12.1%), DUOXA2 (10.3%), and TPO (5.2%). Variants in the genes causing dyshormonogenesis (DH) were more common than those in the genes causing TD (87.9% versus 12.1%). Among the patients with detected variants, 26 (89.7%) were harboring a single gene variant (single-gene group), which include 22 patients harboring biallelic variants (biallelic group) and four patients harboring monoallelic variants (monoallelic group). Three (10.3%) patients harbored variants in two or three genes (multi-gene group or oligogenic group). Compared with the single-gene group, the levothyroxine (L-T4) dose at 1 year of age was higher in the multi-gene group (p = 0.018). A controllable reduction in the L-T4 dose was observed in 25% of patients in the monoallelic group and 59.1% of patients in the biallelic group; however, no patients with such reduction in the L-T4 dose were observed in the oligogenic group.ConclusionsPatients with normal-sized GIS accounted for the majority of our cohort. Genetic defects in the genes causing DH were more common than those in the genes causing TD, with biallelic variants in DUOX2 being dominant. DH might be the leading pathophysiology of CH in Chinese individuals.

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New genetics in congenital hypothyroidism

Cited by 40 publications

References 47 publications

Identification of ZBTB26 as a Novel Risk Factor for Congenital Hypothyroidism

Identification of ZBTB26 as a Novel Risk Factor for Congenital Hypothyroidism

Analysis of Mutation Spectra of 28 Pathogenic Genes Associated With Congenital Hypothyroidism in the Chinese Han Population

Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort

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