scholarly journals Diagnosis of Joubert Syndrome 10 in a Fetus with Suspected Dandy-Walker Variant by WES: A Novel Splicing Mutation in OFD1

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Siyuan Linpeng ◽  
Jing Liu ◽  
Jianyan Pan ◽  
Yingxi Cao ◽  
Yanling Teng ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Novel Mutation ◽  
Joubert Syndrome ◽  
Splicing Mutation ◽  
The Novel ◽  
Rt Pcr ◽  
Abnormal Karyotype ◽  
Whole Exome ◽  
The Family ◽  
Sequencing Result

Joubert syndrome (JBTS) is a clinically and genetically heterogeneous group of ciliary diseases. To date, 34 subtypes of JBTS have been classified due to different causative genes or extra clinical features. Most of them are autosomal recessive, while only the subtype 10 (JBTS10) is a quite rare X-linked recessive disorder caused by OFD1 mutations with few reports. In this study, by using whole exome sequencing (WES), a novel OFD1 splicing mutation (c.2488+2T>C) was identified in a male fetus with suspected Dandy-Walker variant (DWV) and syndactyly, for whom abnormal karyotype and pathogenic CNV have been excluded. This mutation was inherited from the mother who has experienced two similar pregnancies before. An abnormal skipping of exon 18 in OFD1 mRNA was confirmed by RT-PCR and sequencing. Result from quantitative RT-PCR also showed that total OFD1 mRNA in the index fetus was significantly lower than the control. After a combined analysis of genetic testing results and genotype-phenotype correlations, the novel mutation c.2488+2T>C in OFD1 was considered to be the genetic cause for the affected fetus. Thus the diagnosis should be JBTS10 rather than the primary clinical diagnosis of DWV. We report the first prenatal case of JBTS10 in Chinese population, which not only helps the family to predict recurrence risks for future pregnancies but also provides more information for understanding such a rare disease. The results also present evidence that WES is an effective method in prenatal diagnosis for those fetuses with Joubert syndrome.

scholarly journals Delayed diagnosis of Peutz–Jeghers syndrome due to pathological information loss or mistake in family/personal history

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yu-Liang Jiang ◽  
Xiao-Dong Xu ◽  
Bai-Rong Li ◽  
En-Da Yu ◽  
Zi-Ye Zhao ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Novel Mutation ◽  
Delayed Diagnosis ◽  
Personal History ◽  
Pathological Examination ◽  
The Novel ◽  
Novel Mutations ◽  
The Family ◽  
Genetic Level ◽  
Peutz Jeghers Syndrome

Abstract Objective To report Peutz–Jeghers syndrome (PJS) cases with non-definitive clues in the family or personal history and finally diagnosed through pathological examination and STK11 gene mutation test. Clinical presentation and intervention PJS was suspected in 3 families with tortuous medical courses. Two of them had relatives departed due to polyposis or colon cancer without pathological results, and the other one had been diagnosed as hyperplastic polyposis before. Diagnosis of PJS was confirmed by endoscopy and repeated pathological examinations, and the STK11 mutation test finally confirmed the diagnosis at genetic level, during which 3 novel mutation were detected (536C > A, 373_374insA, 454_455insGGAGAAGCGTTTCCCAGTGTGCC). Conclusion Early diagnosis of PJS is important and may be based on a family history with selective features among family members, and the pathological information is the key. The novel mutations also expand the STK11 variant spectrum.

scholarly journals A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Bing-Bing Guo ◽  
Jie-Yuan Jin ◽  
Zhuang-Zhuang Yuan ◽  
Lei Zeng ◽  
Rong Xiang
Keyword(s):  
Extracellular Matrix ◽  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Structure Model ◽  
Whole Exome ◽  
Nucleotide Mutation

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

scholarly journals A novel mutation in the PRPH2 gene in a Chinese pedigree with retinitis pigmentosa and angle-closure glaucoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei-ning Li ◽  
Xiu-juan Du ◽  
Yu-ting Zhang ◽  
Le-yi Wang ◽  
Jing Zhu
Keyword(s):  
Visual Field ◽  
Retinitis Pigmentosa ◽  
Novel Mutation ◽  
Genetic Mutation ◽  
Angle Closure Glaucoma ◽  
Angle Closure ◽  
The Novel ◽  
Progressive Loss ◽  
Whole Exome ◽  
Transversion Mutation

Abstract Background Retinitis pigmentosa (RP) is a rare, progressive, and hereditary disorder that leads to the progressive loss of vision and visual field, and in some cases blindness. The specific relationship between RP and glaucoma has been debated for decades. Methods In this study, we examined a Han RP family with concomitant angle-closure glaucoma (ACG), performed an inductive analysis of their clinical features and assistant results, and applied whole-exome sequencing (WES) technology for a molecular diagnosis. Results A novel transversion mutation (c.626 T > A) was identified in the peripherin-2 (PRPH2) gene in the proband, resulting in the substitution of Valine to aspartic acid in codon 209. A full ophthalmic examination showed that the proband with the c.626 T > A mutation had a typical RP manifestation, with close angles; however, the proband’s elder brother, who lacked the novel mutation, had a normal fundus and open angles. Conclusion Our results extend the genetic mutation spectrum of PRPH2 in RP, and provide evidence to support a genetic correlation between RP and ACG.

Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency and literature review

2021 ◽  
Author(s):  
Rui Zhang ◽  
Yajing Hao ◽  
Ying Xu ◽  
Jiale Qin ◽  
Yanfang Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Sulfite Oxidase ◽  
Loss Of Function ◽  
Oxidase Deficiency ◽  
Neurometabolic Disorders ◽  
Whole Exome ◽  
Sulfite Oxidase Deficiency

Abstract Background: Isolated sulfite oxidase deficiency (ISOD) is the rarest types of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. ISOD is extremely rare and till date only 32 mutations have been identified and reported worldwide. Germline mutation in SUOX gene causes ISOD. Methods: Here, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, respiratory failure, cardiac failure, hyperlactatemia, severe metabolic acidosis, hyperglycemia, hyperkalemia, moderate anemia, atrioventricular block and complete right bundle branch block. Results: Whole exome sequencing identified a novel homozygous transition (c.1227G>A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. Hence, it is a loss-of-function variant. Proband’s father and mother is carrying this novel variant in a heterozygous state. This variant was not identified in 200 ethnically matched normal healthy control individuals. Conclusions: Our study not only expand the mutational spectrum of SUOX gene associated ISOD, but also strongly suggested the application of whole exome sequencing for identifying candidate genes and novel disease-causing mutations.

A novel variant in PAX6 as the cause of aniridia in a Chinese family

2020 ◽  
Author(s):  
Xin Jin ◽  
Wei Liu ◽  
HouBin Huang
Keyword(s):  
Nonsense Mutation ◽  
Novel Mutation ◽  
Causative Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Iris Defect ◽  
The Family ◽  
Novel Variant ◽  
Pax6 Mutation

Abstract Background: Aniridia is a kind of congenital human panocular anomaly, which is related to PAX6 commonly. Methods: A Chinese Aniridia pedigree underwent ophthalmic examinations, including visual acuity, slit lamp and fundoscopy examination. The targeted next-generation sequencing of Aniridia genes was used to identify the causative mutation. Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotypes related to the novel mutation include nystagmus, iris defect, cataract and absence of macular fovea. Conclusion: The novel nonsense mutation in PAX6 was responsible for aniridia phenotype in the family. which expands the spectrum of the PAX6 mutation and its associated phenotype.

Exons sequencing identifies a novel mutation in GPR157 in a high myopia family

2020 ◽  
Author(s):  
Tao Tang ◽  
Mohan Liu ◽  
Ting Wei ◽  
Lin Deng ◽  
Yueyang Zhang ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
High Myopia ◽  
Sanger Sequencing ◽  
Novel Mutation ◽  
Rt Pcr ◽  
Genetic Characteristics ◽  
Reverse Transcription Pcr ◽  
Whole Exome ◽  
Reduced Penetrance ◽  
Next Generation Sequencing Ngs

Abstract Background Next-generation sequencing (NGS) and whole exome sequencing (WES) have identified many potential disease-causing loci and genetic mutations of high myopia(HM). However, these known genes can only explain the heritability of a small proportion of HM patients. A large proportion of variants have yet to be discovered. Herein we aimed to investigate the genetic characteristics of HM through a Chinese HM family(the inheritance pattern unknown) . Methods We performed WES on the parent-offspring trio and identified mutations by Sanger sequencing. All the members in this family were sequenced to validate phenotype co-segregated with candidate genes via Sanger sequencing as well. Besides, mutations detected were further evaluated in a cohort of 110 sporadic high myopia controls and 200 unrelated ethically-matched controls. And reverse transcription PCR(RT-PCR) was applied to measure the mRNA expression levels of GPR157 in the 4-week-old KM mice. Results A novel heterozygous nonsense mutation, c.859C>T (p.Arg287*) of GPR157 gene, was detected in the proband and her father by WES. And this disease-associated mutation was not found in 310 control individuals. For the family under study, HM was classified as autosomal dominant inheritance with reduced penetrance. And RT-PCR results showed GPR157 was abundantly expressed in the eye. Conclusion The hybrid nonsense mutation of the GPR157 gene identified in this study may constitute a novel genetic cause of HM. Keywords :high myopia, WES, GPR157

scholarly journals Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

2019 ◽  
Vol 09 (02) ◽  
pp. 117-120
Author(s):  
Pavalan Selvam ◽  
Shekhar Singh ◽  
Angita Jain ◽  
Herjot Atwal ◽  
Paldeep S. Atwal
Keyword(s):  
Sequence Analysis ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Review Of The Literature ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
The Family ◽  
Type Xi Collagen ◽  
Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

scholarly journals Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2163
Author(s):  
Desaraju Suresh Bhargav ◽  
N. Sreedevi ◽  
N. Swapna ◽  
Soumya Vivek ◽  
Srinivas Kovvali
Keyword(s):  
Exome Sequencing ◽  
Autosomal Recessive ◽  
Frameshift Mutation ◽  
Protein Gene ◽  
Single Gene ◽  
Primary Microcephaly ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
The Family ◽  
Autosomal Recessive Primary Microcephaly

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly.  Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

scholarly journals RHOMutations (p.W126L and p.A346P) in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Satoshi Katagiri ◽  
Takaaki Hayashi ◽  
Masakazu Akahori ◽  
Takeshi Itabashi ◽  
Jo Nishino ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Conformational Transition ◽  
Novel Mutation ◽  
The Novel ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Modeling Analysis ◽  
Whole Exome ◽  
The Impact

Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP).Methods. Whole-exome sequence analysis was performed in ten adRP families. IdentifiedRHOmutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of theRHOmutation on the rhodopsin conformation was examined by molecular modeling analysis.Results. In two adRP families, we identified twoRHOmutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP.Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification ofRHOmutations is a very useful tool for predicting disease severity and providing precise genetic counseling.

scholarly journals Functional Characterization of a Novel Heterozygous Mutation in the Glucokinase Gene That Causes MODY2 in Chinese Pedigrees

2021 ◽  
Vol 12 ◽  
Author(s):  
Feng Jiang ◽  
Jing Yan ◽  
Rong Zhang ◽  
Xiaojing Ma ◽  
Yuqian Bao ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Stability Analysis ◽  
Novel Mutation ◽  
Functional Characterization ◽  
Heterozygous Mutation ◽  
The Novel ◽  
Glucokinase Gene ◽  
Onset Diabetes ◽  
Whole Exome

BackgroundGlucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of GCK can cause a monogenic form of diabetes, maturity-onset diabetes of the young (MODY) directly. In our study, we aimed to explore the mechanism of the novel mutation GCK p.Ala259Thr leading to glucokinase deficiency and hyperglycemia.MethodsThirty early-onset diabetes pedigrees were referred to whole exome sequencing for novel mutations identification. Purified wild-type and mutant GCK proteins were obtained from E.coli systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity.ResultsOne novel missense mutation GCK p.Ala259Thr was identified and co-segregated with diabetes in a Chinese MODY2 pedigree. The kinetic analysis showed that this mutation result in a decreased affinity and catalytic capability for glucose. The thermal stability analysis also indicated that the mutant protein presented dramatically decreased activity at the same temperature.ConclusionOur study firstly identified a novel MODY2 mutation p.Ala259Thr in Chinese diabetes pedigrees. The kinetic and thermal stability analysis confirmed that this mutation caused hyperglycemia through severely damaging the enzyme activities and protein stability.

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