Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening

Yamaguchi, Takeshi; Nakamura, Akie; Nakayama, Kanako; Hishimura, Nozomi; Morikawa, Shuntaro; Ishizu, Katsura; Tajima, Toshihiro

doi:10.1210/clinem/dgaa308

Cited by 45 publications

(50 citation statements)

References 32 publications

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“…This study demonstrated that the frequency of genetic defects in the genes causing TDH was more common than that of the genes causing TD (36/118 (30%) vs 9/118 (8%)) which was in agreement with the previous studies ( 4 , 5 , 22 , 23 , 24 ). The most frequently affected gene in this study was DUOX2 (25 out of 45, 56%).…”

Section: Discussionsupporting

confidence: 92%

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients

Sorapipatcharoen

Tim‐Aroon

Mahachoklertwattana

et al. 2020

Endocrine Connections

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Objective: To identify genetic etiologies of congenital primary hypothyroidism (CH) in Thai patients. Design and methods: CH patients were enrolled. Clinical characteristics including age, signs and symptoms of CH, pedigree, family history, screened thyroid-stimulating hormone results, thyroid function tests, thyroid imaging, clinical course and treatment of CH were collected. Clinical exome sequencing by next-generation sequencing was performed. In-house gene list which covered 62 potential candidate genes related to CH and thyroid disorders was developed for targeted sequencing. Sanger sequencing was performed to validate the candidate variants. Thyroid function tests were determined in the heterozygous parents who carried the same DUOX2 or DUOXA2 variants as their offsprings. Results: There were 118 patients (63 males) included. Mean (SD) age at enrollment was 12.4 (7.9) years. Forty-five of 118 patients (38%) had disease-causing variants. Of 45 variants, 7 genes were involved (DUOX2, DUOXA2, TG, TPO, SLC5A5, PAX8 and TSHR). DUOX2, a gene causing thyroid dyshormonogenesis, was the most common defective gene (25/45, 56%). The most common DUOX2 variant found in this study was c.1588A>T. TG and TPO variants were less common. Fourteen novel variants were found. Thyroid function tests of most parents with heterozygous state of DUOX2 and DUOXA2 variants were normal. Conclusions: DUOX2 variants were most common among Thai CH patients, while TG and TPO variants were less common. The c.1588A>T in DUOX2 gene was highly frequent in this population.

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Section: Discussionsupporting

confidence: 92%

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients

Sorapipatcharoen

Tim‐Aroon

Mahachoklertwattana

et al. 2020

Endocrine Connections

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“…A comprehensive genetic analysis identifies genetic abnormalities in 20% of Japanese patients [ 14 , 15 , 16 , 17 , 18 ]. Mutations in the DUOX2 gene are particularly common, identified in approximately 20% cases of dyshormonogenesis.…”

Section: Epidemiology Of Ch In Japanmentioning

confidence: 99%

Newborn Screening for Congenital Hypothyroidism in Japan

Minamitani

2021

IJNS

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Congenital hypothyroidism (CH) is the most common preventable cause of intellectual impairment or failure to thrive by early identification and treatment. In Japan, newborn screening programs for CH were introduced in 1979, and the clinical guidelines for newborn screening of CH were developed in 1998, revised in 2014, and are currently undergoing further revision. Newborn screening strategies are designed to detect the elevated levels of thyroid stimulating hormone (TSH) in most areas of Japan, although TSH and free thyroxine (FT4) are often measured simultaneously in some areas. Since 1987, in order not to observe the delayed rise in TSH, additional rescreening of premature neonates and low birth weight infants (<2000 g) at four weeks of life or when their body weight reaches 2500 g has been recommended, despite a normal initial newborn screening. Recently, the actual incidence of CH has doubled to approximately 1:2500 in Japan as in other countries. This increasing incidence is speculated to be mainly due to an increase in the number of mildly affected patients detected by the generalized lowering of TSH screening cutoffs and an increase in the number of preterm or low birth weight neonates at a higher risk of having CH than term infants.

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“…Several studies have screened for CH genetic mutations by NGS, with differences in populations, subjects, study methods, genes, and pathogenicity criteria [3,4,[13][14][15]. We included CH patients of various classifications, such as PCH, TCH, and SCH.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic diagnosis of CH is helpful in understanding its genetic etiology. Recently, mutations associated with CH have been identified in several studies using next generation sequencing (NGS) [3,4,[13][14][15]. Although NGS remains the most reliable technique in identifying sequence variants, it is inefficient as it requires a large number of samples for one measurement.…”

mentioning

confidence: 99%

Screening of frequent variants associated with congenital hypothyroidism: a comparison with next generation sequencing

et al. 2021

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Congenital hypothyroidism (CH) is considered the most common congenital endocrine disorder of genetic origin. Next generation sequencing (NGS) is the standard method for identifying genetic mutations, but it is an expensive and complex technique. Therefore, we propose to use Sanger sequencing to identify selected variants of the four most common CH-causative genes: DUOX2, TG, TSHR, and PAX8. To analyze the performance of Sanger sequencing, we compared its variant detection ability with that of a CH NGS panel containing 53 genes. We performed Sanger sequencing of selected variants and panel NGS analysis of 25 Japanese patients with CH. Sanger sequencing identified nine variants in seven patients, while NGS identified 24 variants in 14 patients. Of these, eight, five, eight, two, and one were found to be potentially pathogenic in DUOX2, TSHR, TG, UBR1, and TPO genes, respectively. The percentage of detectable variants using Sanger sequencing compared with NGS was 37.5% (9/24 variants), whereas the percentage of detectable cases carrying variants using Sanger sequencing compared with NGS was 50% (7/14 patients). We proposed a system for screening commonly identified CH-related variants by Sanger sequencing. Sanger sequencing could therefore identify about a third of CH-causative variants, so is considered an effective and efficient form of pre-screening before NGS.

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Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening

Cited by 45 publications

References 32 publications

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients

Newborn Screening for Congenital Hypothyroidism in Japan

Screening of frequent variants associated with congenital hypothyroidism: a comparison with next generation sequencing

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