Genetic and Clinical Characteristics of Korean Patients with Isolated Hypoparathyroidism: From the Korean Hypopara Registry Study

Abstract

Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.

Genetic Screening in a Large Chinese Cohort of Childhood Onset Hypoparathyroidism by Next-Generation Sequencing Combined with TBX1-MLPA

“…In previous studies from different centers with different candidate genes and by different methods, the detection rate of childhood onset HP varied. First, a study from Korea included 20 probands with 17 sporadic cases and three familial HP, with an onset prior to 18 years old in four probands (two familial HP) . Whole‐exome sequencing was performed in one childhood onset proband with familial HP, and Sanger sequencing of GCM2 , CASR , and PTH was performed in all four patients.…”

“…First, a study from Korea included Table 2 20 probands with 17 sporadic cases and three familial HP, with an onset prior to 18 years old in four probands (two familial HP). (16) Whole-exome sequencing was performed in one childhood onset proband with familial HP, and Sanger sequencing of GCM2, CASR, and PTH was performed in all four patients. They found one novel GCM2 and one recurrent CASR mutation.…”

“…Because of the rarity of the disease, previous mutation screening studies for HP have primarily focused on only one or several genes . Studies using comprehensive genetic screening in patients with HP are still lacking, and sample sizes of previous studies have been limited.…”

“…(11)(12)(13)(14)(15) Because of the rarity of the disease, previous mutation screening studies for HP have primarily focused on only one or several genes. (7,8,16) Studies using comprehensive genetic screening in patients with HP are still lacking, and sample sizes of previous studies have been limited. Therefore, in this study we investigated the genetic background in a large cohort of childhood onset Chinese HP patients (17) through targeted next-generation sequencing (NGS) combined with multiplex ligation-dependent probe amplification (MLPA) of the TBX1 gene.…”

Short stature and hypoparathyroidism in a child with Kenny-Caffey syndrome type 2 due to a novel mutation in FAM111A gene

“…It is characterized by low or normal parathyroid hormone (PTH) levels in the presence of hypocalcemia and hyperphosphatemia. Although commonly seen as an iatrogenic complication following anterior neck surgery in adults, the etiology of hypoparathyroidism in children is more diverse and includes a heterogeneous group of disorders, many of which have a genetic basis [2, 3]. An increased understanding of the genetic etiology and improved genetic testing has provided an opportunity to expand the molecular diagnosis of hypoparathyroidism [2].…”