Chromosomal microarray and whole exome sequencing identify genetic causes of congenital hypothyroidism with extra-thyroidal congenital malformations

Chunyun Fu; Shiyu Luo; Yue Zhang; Xin Fan; Alissa M D'Gama; Xiaofei Zhang; Haiyang Zheng; Jiasun Su; Chuan Li; Jingsi Luo; Pankaj B Agrawal; Qifei Li; Shaoke Chen

doi:10.1016/j.cca.2018.11.035

Chromosomal microarray and whole exome sequencing identify genetic causes of congenital hypothyroidism with extra-thyroidal congenital malformations

Clin Chim Acta. 2019 Feb:489:103-108. doi: 10.1016/j.cca.2018.11.035. Epub 2018 Nov 30.

Authors

Chunyun Fu¹, Shiyu Luo², Yue Zhang², Xin Fan², Alissa M D'Gama³, Xiaofei Zhang², Haiyang Zheng², Jiasun Su², Chuan Li², Jingsi Luo², Pankaj B Agrawal⁴, Qifei Li⁵, Shaoke Chen⁶

Affiliations

¹ Medical Science Laboratory, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China.
² Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China.
³ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: pagrawal@enders.tch.harvard.edu.
⁵ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: Qifei.Li@childrens.harvard.edu.
⁶ Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China. Electronic address: chenshaoke123@163.com.

PMID: 30508507
DOI: 10.1016/j.cca.2018.11.035

Abstract

Background: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder. Although most patients present with isolated CH, some patients present with CH and extra-thyroidal congenital malformations (ECMs), for which less is known about the underlying genetics. The aim of this study was to investigate the genetic mechanisms in patients with CH and ECMs using chromosomal microarray (CMA) and whole exome sequencing (WES).

Methods: Peripheral venous blood samples were collected from 16 patients with CH and ECMs. Genomic DNA was extracted from peripheral blood leukocytes. CMA and WES were performed to detect copy number and single nucleotide variants.

Results: CMA identified clinically significant copy number variants in 7 patients consistent with their phenotypes. For 6 of them, the genotype and phenotype suggested a syndromic diagnosis, and the remaining patient carried a pathogenic microdeletion and microduplication including GLIS3. WES analysis identified 9 different variants in 7 additional patients. The variants included 2 known mutations (c.1096C>T (p.Arg366Trp) in KCNQ1 and c.848C>A (p.Pro283Gln) in NKX2-5) and 7 novel variants: one nonsense mutation (c.4330C>T (p.Arg1444*) in ASXL3), one frameshift mutation (c.1253_1259delACTCTGG (p.Asp418fs) in TG), three missense variants (c.1472C>T (p.Thr491Ile) in TG, c.4604A>G (p.Asp1535Gly) in TG, and c.2139G>T (p.Glu713Asp) in DUOX2, and two splice site variants (c.944-1G>C and c.3693 + 1G>T) in DUOX2.

Conclusions: We report the first genetic study of CH patients with ECMs using CMA and WES. Overall, our detection rate for pathogenic and possibly pathogenic variants was 87.5% (14/16). We report 7 novel variants, expanding the mutational spectrum of TG, DUOX2, and ASXL3.

Keywords: ASXL3; Chromosomal microarray; Congenital hypothyroidism; DUOX2; Extra-thyroidal congenital malformations; GLIS3; KCNQ1; NKX2-5; TG; Whole exome sequencing.

MeSH terms

Child
Chromosomes, Human / genetics*
Congenital Hypothyroidism / complications
Congenital Hypothyroidism / etiology
Congenital Hypothyroidism / genetics*
Exome Sequencing*
Humans
Infant
Mutation
Oligonucleotide Array Sequence Analysis*