Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature

Gui, Baoheng; Yu, Chenxi; Li, Xiaoxin; Zhao, Sen; Zhao, Hengqiang; Yan, Zihui; Cheng, Xi; Lin, Jiachen; Zheng, Hongliang; Shao, Jiashen; Zhao, Ziran; Zhao, Lina; Niu, Yuchen; Zhao, Zhi Gang; Wang, Huizi; Xie, Bobo; Wei, Xiaojun; Gui, Chunrong; Li, Chuan; Chen, Shaoke; Wang, Yi; Song, Yanning; Gong, Chunxiu; Zhang, Terry Jianguo; Fan, Xin; Wu, Zhihong; Chen, Yujun; Wu, Nan

doi:10.3389/fcell.2021.661747

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…To date, pathogenic variants of the ROR2 receptor have been associated with Brachydactyly B (OMIM # 113000) and Robinow syndrome (OMIM # 268310), in which some individuals show dental problems such as delayed eruption and delayed root formation of permanent teeth [ 37 ]. Recent findings indicate that heterozygous recurrent nucleotide alternations, including the p.Gly559Ser missense variant located within the ROR2 kinase domain, might also be associated with isolated short stature [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Biedziak

Firlej

Dąbrowska

et al. 2022

JCM

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Non-syndromic tooth agenesis (ns-TA) is one of the most common dental anomalies characterized by the congenital absence of at least one permanent tooth (excluding third molars). Regarding the essential role of genetic factors in ns-TA aetiology, the present study aimed to identify novel pathogenic variants underlying hypodontia and oligodontia. In a group of 65 ns-TA patients and 127 healthy individuals from the genetically homogenous Polish population, the coding sequences of 423 candidate genes were screened using targeted next-generation sequencing. Pathogenic and likely pathogenic variants were identified in 37 (56.92%) patients, including eight nucleotide alternations of genes not previously implicated in ns-TA (CHD7, CREBBP, EVC, LEF1, ROR2, TBX22 and TP63). However, since only single variants were detected, future research is required to confirm and fully understand their role in the aetiology of ns-TA. Additionally, our results support the importance of already known ns-TA candidate genes (AXIN2, EDA, EDAR, IRF6, LAMA3, LRP6, MSX1, PAX9 and WNT10A) and provide additional evidence that ns-TA might be an oligogenic condition involving the cumulative effect of rare variants in two or more distinct genes.

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Section: Discussionmentioning

confidence: 99%

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Biedziak

Firlej

Dąbrowska

et al. 2022

JCM

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“…Demographic information, physical examination results and clinical symptoms were taken into account. Details of cohort were reported in the previous study ( 18 , 19 ).…”

Section: Methodsmentioning

confidence: 99%

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

Xie

Zhao

et al. 2021

Front. Endocrinol.

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PurposeCongenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis.MethodsWe retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis.ResultsIn 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients.ConclusionOur study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

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“…The most common cause of monogenic short stature is the deficiency of the short-stature homeobox-containing (SHOX) gene ( Marchini et al, 2016 ; Ponomarenko et al, 2020 ). A study revealed newer mechanistic insights that identified c.1675G > A mutation in receptor tyrosine kinase-like orphan receptor 2 (ROR2) in patients with short stature ( Gui et al, 2021 ). To date, key molecular mechanisms underlying stunted growth and childhood short stature remain equivocal.…”

Section: Introductionmentioning

confidence: 99%

Serum Metabonomics Reveals Key Metabolites in Different Types of Childhood Short Stature

et al. 2022

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Nowadays, short stature (SS) in childhood is a common condition encountered by pediatricians, with an increase in not just a few families. Various studies related to the variations in key metabolites and their biological mechanisms that lead to SS have increased our understanding of the pathophysiology of the disease. However, little is known about the role of metabolite variation in different types of childhood SS that influence these biological processes and whether the understanding of the key metabolites from different types of childhood SS would predict the disease progression better. We performed a systematic investigation using the metabonomics method and studied the correlation between the three groups, namely, the control, idiopathic short stature (ISS), and short stature due to growth hormone deficiency (GHD). We observed that three pathways (viz., purine metabolism, sphingolipid signaling pathway, and sphingolipid metabolism) were significantly enriched in childhood SS. Moreover, we reported that two short peptides (Thr Val Leu Thr Ser and Trp Ile Lys) might play a significant role in childhood SS. Various metabolites in different pathways including 9,10-DiHOME, 12-HETE, 12(13)-EpOME, arachidonic acid methyl ester, glycerophospho-N-arachidonoyl ethanolamine, curvulinic acid (2-acetyl-3,5-dihydroxyphenyl acetic acid), nonanoic acid, and N'-(2,4-dimethylphenyl)-N-methylformamidine in human serum were compared between 60 children diagnosed with SS and 30 normal-height children. More investigations in this area may provide insights and enhance the personalized treatment approaches in clinical practice for SS by elucidating pathophysiology mechanisms of experimental verification.

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Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature

Cited by 5 publications

References 37 publications

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

Serum Metabonomics Reveals Key Metabolites in Different Types of Childhood Short Stature

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