Journal Article

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis

Alzahrani, Ali S, Al-Odaib, Ali, Kattan, Walaa E, Shi, Yufei, Meyer, Brian F, Babiker, Omer, Alqahtani, Mohammad A, Al-Rijjal, Roua A, Al Qarni, Ali, Al-Faham, Manar S A, Zou, Minjing, BinEssa, Huda A, Al-Enezi, Anwar F, Baitei, Essa Y, Alsagheir, Afaf

2018

Overview

Abstract Context Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective To identify the mutation spectrum of CH-causing genes. Methods Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis. The mutation spectrum was analyzed by NGS in 55 Saudi patients with CH. The most common mutations were TG and TSHR. SLC26A7 appears to be associated with thyroid hormone synthesis.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Adolescent / Antiporters - genetics / Child / Child, Preschool / Congenital diseases / Congenital Hypothyroidism - diagnosis / Congenital Hypothyroidism - genetics / Consanguinity / DNA Mutational Analysis / Endocrine disorders / Family / Female / High-Throughput Nucleotide Sequencing / Humans / Hypothyroidism / Infant / Infant, Newborn / Male / Medical screening / Molecular Diagnostic Techniques - methods / Mutation / Neonatal Screening - methods / Neonates / Pax8 protein / Pedigree / Saudi Arabia / Sulfate Transporters - genetics / Thyroid / Thyroid Dysgenesis - genetics / Thyroid gland / Thyroid transcription factor 1 / Thyroid-stimulating hormone receptors / Whole genome sequencing / Young Adult