scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Metaphyseal Chondrodysplasia ◽  
Whole Exome ◽  
Col10a1 Gene ◽  
Silico Analysis ◽  
Nc1 Domain

Abstract Background: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 normal control donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results: We found that the phenotype of affected family members exhibited irregular dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of irregular dominance in MCDS.

scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Metaphyseal Chondrodysplasia ◽  
Whole Exome ◽  
Healthy Donors ◽  
Col10a1 Gene ◽  
Nc1 Domain

Abstract Background: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results: We found that the phenotype of affected family members exhibited irregular dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of irregular dominance in MCDS.

scholarly journals Exome sequencing identified two novel COL10A1 heterozygous mutations in two irregular dominance Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Metaphyseal Chondrodysplasia ◽  
Whole Exome ◽  
Col10a1 Gene ◽  
Nc1 Domain

Abstract Background Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, the research about unusual phenotype features of MCDS is rare. Methods Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals underwent whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and 250 donors. Then the spatial model of type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results We found that the affected family members exhibited evident irregular dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be remarkably deleterious in silico analysis. Furthermore, protein modeling revealed that the two substitutions located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in pericellular matrix. Conclusion Two novel mutations were identified in the present study, which facilitated to diagnose MCDS and further expanded the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research preliminarily elaborated the phenotype features and heredity characteristics of MCDS based on the two Chinese pedigrees.

scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Incomplete Dominance ◽  
Metaphyseal Chondrodysplasia ◽  
Healthy Donors ◽  
Col10a1 Gene ◽  
Nc1 Domain

Abstract Background: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results: We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.

scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Incomplete Dominance ◽  
Metaphyseal Chondrodysplasia ◽  
Healthy Donors ◽  
Col10a1 Gene ◽  
Nc1 Domain

Abstract Background: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results: We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.

scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Incomplete Dominance ◽  
Metaphyseal Chondrodysplasia ◽  
Whole Exome ◽  
Healthy Donors ◽  
Nc1 Domain

Abstract Background Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T > A (p.Phe589Ile)] and [c.1846A > G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.

scholarly journals A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2498-2498
Author(s):  
Shreerang Sirdesai ◽  
Kerryn Weekes ◽  
Asif Alam ◽  
Huyen A Tran ◽  
Christopher Barnes ◽  
...  
Keyword(s):  
In Silico ◽  
Family Members ◽  
In Silico Analysis ◽  
Clinical Severity ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Mild Phenotype ◽  
Genotype Phenotype Correlation ◽  
Silico Analysis

Abstract Aim: Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients. Methods: Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1. Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor. Results: 318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1) In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA. 20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations. Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care Conclusion: This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally. Disclosures No relevant conflicts of interest to declare.

scholarly journals In silico analysis of missense mutations in exons 1–5 of the F9 gene that cause hemophilia B

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lennon Meléndez-Aranda ◽  
Ana Rebeca Jaloma-Cruz ◽  
Nina Pastor ◽  
Marina María de Jesús Romero-Prado
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Silico Analysis

scholarly journals Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension

2020 ◽  
Vol 33 (7) ◽  
pp. 670-675
Author(s):  
Peng Fan ◽  
Xiao-Cheng Pan ◽  
Di Zhang ◽  
Kun-Qi Yang ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Early Onset ◽  
In Silico ◽  
Genetic Diagnosis ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Chinese Family ◽  
Clinical Genetic ◽  
Autosomal Dominant Disorder ◽  
Liddle Syndrome ◽  
Silico Analysis

Abstract BACKGROUND Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.

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