Identification of &lt;b&gt;&lt;i&gt;Transient Receptor Potential Channel 4-Associated Protein&lt;/i&gt;&lt;/b&gt; as a Novel Candidate Gene Causing Congenital Primary Hypothyroidism

Choukair, Daniela; Eberle, Birgit; Vick, Philipp; Hermanns, Pia; Weiß, Birgit; Paramasivam, Nagarajan; Schlesner, Matthias; Lornsen, Katharina; Roeth, Ralph; Klutmann, Carina; Kreis, Jennifer; Hoffmann, Georg F.; Pohlenz, Joachim; Rappold, Gudrun; Bettendorf, Markus

doi:10.1159/000507114

Cited by 9 publications

(7 citation statements)

References 35 publications

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“…Heterozygous C‐to‐T transversion at codon 31 in the PAX8 gene‐paired domain causes substitution of a cysteine residue for an arginine residue, which has been reported to impair the function of transactivation 7,28 . De novo variant in genes related to TD was occasionally reported in CH patients 29,30 but could not be the common contributor to CH.…”

Section: Discussionmentioning

confidence: 98%

The mutation screening in candidate genes related to thyroid dysgenesis by targeted next‐generation sequencing panel in the Chinese congenital hypothyroidism

Zhang

Yang

Cheng

et al. 2021

Clinical Endocrinology

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Objective Congenital hypothyroidism (CH) is known to be due to thyroid dyshormonogenesis (DH), which is mostly inherited in an autosomal recessive inheritance pattern or thyroid dysgenesis (TD), whose inheritance pattern is controversial and whose molecular etiology remains poorly understood. Design and Methods The variants in 37 candidate genes of CH, including 25 genes related to TD, were screened by targeted exon sequencing in 205 Chinese patients whose CH cannot be explained by biallelic variants in genes related to DH. The inheritance pattern of the genes was analyzed in family trios or quartets. Results Of the 205 patients, 83 patients carried at least one variant in 19 genes related to TD, and 59 of those 83 patients harbored more than two variants in distinct candidate genes for CH. Biallelic or de novo variants in the genes related to TD in Chinese patients are rare. We also found nine probands carried only one heterozygous variant in the genes related to TD that were inherited from a euthyroid either paternal or maternal parent. These findings did not support the monogenic inheritance pattern of the genes related to TD in CH patients. Notably, in family trio or quartet analysis, of 36 patients carrying more than two variants in distinct genes, 24 patients carried these variants inherited from both their parents, which indicated that the oligogenic inheritance pattern of the genes related to TD should be considered in CH. Conclusions Our study expanded the variant spectrum of the genes related to TD in Chinese CH patients. It is rare that CH in Chinese patients could be explained by monogenic germline variants in genes related to TD. The hypothesis of an oligogenic origin of the CH should be considered.

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Section: Discussionmentioning

confidence: 98%

The mutation screening in candidate genes related to thyroid dysgenesis by targeted next‐generation sequencing panel in the Chinese congenital hypothyroidism

Zhang

Yang

Cheng

et al. 2021

Clinical Endocrinology

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“…Since the identification of the first causal gene for thyroid dysgenesis PAX8 in 1998 [ 18 ], a number of genes underlying congenital primary hypothyroidism (CH) have been reported to play a role in this phenotype (e.g., TSHR, NKX2-1, NKX2-5, FOXE1, GLIS3, JAG1, TBX1, NTN1, CDCA8, HOXD3, HOXB3, CDCH8, TUBB1 , and TRPC4AP ) [ 5 , 19 , 20 ]. These advances have contributed to our understanding of thyroid development and provided very useful information for genetic diagnosis.…”

Section: Discussionmentioning

confidence: 99%

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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“…A first de novo TRPC4AP mutation has been identified using WES in a child with TD. 17 Next, 179 patients with CHTD were sequenced using a panel of target genes making it possible to find four variants in TRPC4AP . During development, Choukair et al .…”

Section: Recently Discovered Genes Involved In Primary Chmentioning

confidence: 99%

Genetics of congenital hypothyroidism: Modern concepts

Stoupa

Kariyawasam

Polak

et al. 2022

Pediatric Investigation

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Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, highthroughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.

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Identification of <b><i>Transient Receptor Potential Channel 4-Associated Protein</i></b> as a Novel Candidate Gene Causing Congenital Primary Hypothyroidism

Cited by 9 publications

References 35 publications

The mutation screening in candidate genes related to thyroid dysgenesis by targeted next‐generation sequencing panel in the Chinese congenital hypothyroidism

The mutation screening in candidate genes related to thyroid dysgenesis by targeted next‐generation sequencing panel in the Chinese congenital hypothyroidism

Identification of ZBTB26 as a Novel Risk Factor for Congenital Hypothyroidism

Genetics of congenital hypothyroidism: Modern concepts

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