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

Abstract

At least 15 candidate genes have been implicated in hypoparathyroidism (HP). However, comprehensive screening of causative genes for HP is lacking. Here, we investigated the genotype spectrum in a large group of Chinese patients with childhood onset HP. A total of 173 patients with childhood onset HP were analyzed using targeted next‐generation sequencing (NGS), including 15 candidate genes combined with multiplex ligation‐dependent probe amplification (MLPA) of the TBX1 gene. Twenty‐seven pathogenic or likely pathogenic mutations in five genes (TBX1, AIRE, GATA3, FAM111A, and CASR) including 13 novel variants in 23 patients, and 12 variants of uncertain clinical significance in five genes (GATA3, CASR, FAM111A, GCM2, and PTH) in 11 patients, were identified by NGS. Additionally, an entire gene deletion of TBX1 in 25 patients was found by TBX1‐MLPA. Combined with clinical data, 26 (15.0%) cases of DiGeorge syndrome (OMIM #188400), nine (5.2%) autoimmune polyglandular syndrome type 1 (OMIM #240300), eight (4.6%) autosomal dominant hypocalcemia type 1 (OMIM #601198), four (2.3%) hypoparathyroidism‐deafness‐renal dysplasia syndrome (OMIM #146255), and one (0.6%) Kenny‐Caffey syndrome type 2 (OMIM #127000) were verified. Among them, 16 of 26 (61.5%) DiGeorge syndrome cases were undiagnosed due to the lack of obvious clinical clues before genetic testing. The onset age of patients with mutations (median [interquartile range], 2.8 [0.1, 9.6] years) was significantly earlier than those without mutations (13.0 [8.8, 15.0] years) (p < 0.001). Family history, early onset age, especially prior to 5 years old, and extraparathyroid manifestations were clues for hereditary HP. The combined targeted NGS and TBX‐1 MLPA were conveniently and effectively used for comprehensive genetic screening in this large Chinese cohort of childhood onset HP patients. Genetic defects were identified in 27.7% of early‐onset HP patients, including four kinds of syndromic HP and one isolated HP. A total of 13 novel mutations were detected, which expands the mutation spectrum of hypoparathyroidism. © 2019 American Society for Bone and Mineral Research.

Overlapping phenotype comprising Kenny‐Caffey type 2 and Sanjad‐Sakati syndromes: The first case report

“…revealed in the present study has been previously reported in 14 cases worldwide (Abraham et al, 2017;Grosse et al, 2017;Guo et al, 2014;Isojima et al, 2014;Nikkel et al, 2014;Unger et al, 2013;Wang et al, 2019;Yerawar, Kabde, & Deokar, 2020).…”

“…The variable ID phenotype in KCS1 and SSS has been reported worldwide (Albaramki et al, 2012; Diaz et al, 1999; Haider et al, 2014; Kelly, 2000; Sanjad et al, 1991). The heterozygous de novo c.1706G>A (p.Arg569His) variant in FAM111A revealed in the present study has been previously reported in 14 cases worldwide (Abraham et al, 2017; Grosse et al, 2017; Guo et al, 2014; Isojima et al, 2014; Nikkel et al, 2014; Unger et al, 2013; Wang et al, 2019; Yerawar, Kabde, & Deokar, 2020). None of these patients were described with microcephaly and/or ID, and most were independent studies, with no familial relationship between the patients, except a report on a mother and daughter by Nikkel et al (2014).…”

Characterization of the clinical and genetic spectrum of autoimmune polyendocrine syndrome type 1 in Chinese case series

“…In our study, hypoparathyroidism occurred in 92.3% of the patients between the ages of four to 18 years (mean 8.6 ± 3.9 years) and was the first symptom of the triad in about 70% of patients. Previous studies have identified that APS1 accounts for 2.7%–5.2% in childhood-onset patients with hypoparathyroidism [ 9 , 10 ]. Therefore, all childhood-onset patients with hypoparathyroidism should be systematically evaluated for evidence of APS1, and long-term follow-up was necessary.…”

Hypoparathyroidism, deafness, and renal dysplasia syndrome: 20 Years after the identification of the firstGATA3mutations

“…Other studies of families with apparently isolated autosomal dominant hearing loss, using NGS panels, revealed that the cause of the deafness was GATA3 mutations and that other previously undetected HDR features were also present (Lin et al, 2015;L. Wang et al, 2017 Wang et al, 2019). In another study, 37 patients with pediatric hypoparathyroidism were sequenced for five candidate genes and GATA3 mutations were identified in 5 patients (Kim et al, 2015).…”

“…respectively. However, it should be noted that the great majority of patients with isolated hypoparathyroidism or isolated renal dysplasia that were found to have GATA3 mutations, either had incomplete clinical information about other organs or were found to have other features of HDR when examined more closely (e.g., by carrying out formal hearing evaluation) (Hwang et al, 2014;Kim et al, 2015;Sanna-Cherchi et al, 2017;Y. Wang et al, 2019).…”