scholarly journals Mutation detection and prenatal diagnosis of XLHED pedigree

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3691 ◽  
Author(s):  
Yao Lin ◽  
Wei Yin ◽  
Zhuan Bian
Keyword(s):  
Prenatal Diagnosis ◽  
Structural Changes ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Premature Stop Codon ◽  
Deciduous Teeth ◽  
Chinese Family ◽  
Female Carrier ◽  
Causative Gene

Background The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED. Methods The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene’s promoter was evaluated by pyrosequencing. Results This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene’s promoter was not related to carriers’ phenotype changes in this family. Discussion We reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.

scholarly journals A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia

2019 ◽  
Vol 32 (8) ◽  
pp. 752-758
Author(s):  
Peng Fan ◽  
Yu-Mo Zhao ◽  
Di Zhang ◽  
Ying Liao ◽  
Kun-Qi Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Single Gene ◽  
Family Members ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
Autosomal Dominant Disorder ◽  
Liddle Syndrome ◽  
Genetic Sequencing

Abstract BACKGROUND Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.

scholarly journals Truncated Epithelial Sodium Channel β Subunit Responsible for Liddle Syndrome in a Chinese Family

2019 ◽  
Vol 44 (5) ◽  
pp. 942-949
Author(s):  
Peng Fan ◽  
Chao-Xia Lu ◽  
Kun-Qi Yang ◽  
Pei-Pei Lu ◽  
Su-Fang Hao ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Sodium Channel ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Epithelial Sodium Channel ◽  
Chinese Family ◽  
Liddle Syndrome ◽  
Direct Dna Sequencing ◽  
Py Motif

Background/Aims: Liddle syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. Methods: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the β-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. Results: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated β-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. Conclusions: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of β-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.

scholarly journals A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 411
Author(s):  
María Lachgar ◽  
Matías Morín ◽  
Manuela Villamar ◽  
Ignacio del Castillo ◽  
Miguel Ángel Moreno-Pelayo
Keyword(s):  
Hearing Loss ◽  
Stop Codon ◽  
Coiled Coil ◽  
Premature Stop Codon ◽  
Scaffolding Protein ◽  
Common Mechanism ◽  
Chinese Family ◽  
Truncating Mutation ◽  
Spanish Family ◽  
Sensory Defect

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

Noval Mutation in Four Saudi Families with Glanzmann Thrombasthenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1136-1136
Author(s):  
Tarek Owaidah ◽  
Hala Abalkhail ◽  
Abdulrahman Al Musa ◽  
Hasan Mosmali ◽  
Albanyan Abdulmajeed ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Family Members ◽  
Premature Stop Codon ◽  
Type I ◽  
Bleeding Tendency ◽  
Coding Region ◽  
Glanzmann Thrombasthenia ◽  
Exon 1

Abstract Abstract 1136 Introduction: Glanzmann thrombasthenia (GT) is a rare autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation and variable bleeding tendency. Inherited genetic mutations in integrin alpha IIb and beta3 (ITGA2B, ITGB3) result in a heterogeneity of the thrombasthenia phenotypes. It is phenotypically expressed in homozygotes or compound heterozygotes, given that 50% of normal aIIbb3 is sufficient to guarantee unimpaired platelet function that result in asymptomatic carriers. Defects in ITGB3 result in failure of binding of B3 and alpha IIb. These defects had been reported in Arabs (Iraqi Jews). We are reporting some results of Saudi GT genotype project. Materials & Methods: In this study, we analyzed the entire coding region ITGB3 gene using polymerase chain reaction (PCR) and direct sequencing with primers specifically designed to amplify the coding region of exon 1–15 and exon /Intron boundaries in a cohort of 51 GT patients diagnosed and treated in our institute. Results: Out of 51 cases from 20 families had mutational screening of the ITGB3 gene with the aim to detect the causative pathogenic mutations to enable the pre-symptomatic diagnosis in at risk family members. In this study we detect 1 novel germline mutation c.2190delC (p.Ser703fs) in exon 13. The mutation is predicted to result in premature stop codon and protein truncation. The mutation was detected in 6 patients in homozygous stat (3 males and 3 females). Three tested samples from the patients family members detected the mutation in heterozygous state and all of them were asymptomatic with normal PFA and Intact expression of Platelet Glycoprotiens CD41(Gpllb), CD42a(GPIX), CD42b(GPlb), and CD61(Gpllla). All the GT patients with this mutation were type I GT with Prolonged PFA and complete absence of CD41(Gpllb) and CD61(Gpllla) glycoprotein. Conclusion: The result of this study represents the first Molecular analysis of ITGB3 gene in Saudi Arabia and displays the existence of novel pathogenic and possibly a founder effect in Saudi families. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Truncating Mutation in FOXC2 Gene in Familial Hemorrhoids and Varicose Veins

2020 ◽  
Vol 14 ◽  
Keyword(s):  
Frameshift Mutation ◽  
Stop Codon ◽  
Varicose Veins ◽  
Premature Stop Codon ◽  
Genetic Mutations ◽  
Physiological Factors ◽  
Vascular Integrity ◽  
Truncating Mutation ◽  
Two Samples

Hemorrhoids and varicose veins are conditions resulting from loss of vascular integrity and, despite being worldwide health concerns, their pathogenesis has not been clearly defined. Many risk factors have been linked to the development of these complications including diet, defecating habits, alcohol consumption and other physiological factors. There are limited studies involving the possible role of genetic mutations in the development of hemorrhoids and varicose veins. FoxC2 is an important transcription factor that plays many roles in a variety of embryonic developmental processes, including angiogenesis. In the current study, we aimed to investigate the role of the FOXC2 gene variations in the development of familial hemorrhoids and varicose veins in the Jordanian population. Thirty-two samples were collected from eight families manifested hemorrhoids and/or varicose veins conditions. DNA sequencing was performed to screen variation in the FOXC2 gene. Two individuals with severe and early onset of hemorrhoids and varicose veins from the same family showed a frameshift mutation (881'inT) in the coding exon of the FOXC2 gene resulting in a premature stop codon at position +1386 (294 residues truncated peptide). In conclusion, our results support a possible role of genetic predisposition in the development of hemorrhoids and varicose veins with a frequency of 6% in the selected population

scholarly journals Band 3 Campinas: A Novel Splicing Mutation in the Band 3 Gene (AE1 ) Associated With Hereditary Spherocytosis, Hyperactivity of Na+/Li+ Countertransport and an Abnormal Renal Bicarbonate Handling

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2810-2818 ◽  
Author(s):  
Paulo R.M. Lima ◽  
José A.R. Gontijo ◽  
José B. Lopes de Faria ◽  
Fernando F. Costa ◽  
Sara T.O. Saad
Keyword(s):  
Hereditary Spherocytosis ◽  
Stop Codon ◽  
Collecting Duct ◽  
Direct Sequencing ◽  
Donor Site ◽  
Premature Stop Codon ◽  
Band 3 ◽  
Base Substitution ◽  
Molecular Defect ◽  
Urinary Acidification

Abstract We have studied the molecular defect underlying band 3 deficiency in one family with hereditary spherocytosis using nonradioactive single strand conformation polimorphism of polymerase chain reaction (PCR) amplified genomic DNA of the AE1 gene. By direct sequencing, a single base substitution in the splicing donor site of intron 8 (position + 1G → T) was identified. The study of the cDNA showed a skipping of exon 8. This exon skipping event is responsible for a frameshift leading to a premature stop codon 13 amino acids downstream. The distal urinary acidification test by furosemide was performed to verify the consequences of the band 3 deficiency in α intercalated cortical collecting duct cells (αICCDC). We found an increased basal urinary bicarbonate excretion, associated with an increased basal urinary pH and an efficient distal urinary acidification. We also tested the consequences of band 3 deficiency on the Na+/H+ exchanger, by the measurement of Na+/Li+ countertransport activity in red blood cells. The Na+/Li+ countertransport activity was increased threefold to sixfold in the patients compared with the controls. It is possible that band 3 deficiency in the kidney leads to a decrease in the reabsorption of HCO−3 in αICCDC and anion loss, which might be associated with an increased sodium-lithium countertransport activity.

A Novel IRF6 Frameshift Mutation in a Large Chinese Pedigree With Van der Woude syndrome

2021 ◽  
pp. 105566562110109
Author(s):  
Qi Peng ◽  
Wenyan Qin ◽  
Siping Li ◽  
Meihua Huang ◽  
Chunbao Rao ◽  
...  
Keyword(s):  
Stop Codon ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
The Novel ◽  
Protein Alignment ◽  
Van Der Woude Syndrome ◽  
Psychological Burden ◽  
Irf6 Gene

Aims: Van der Woude syndrome (VWS) is one of the most common craniofacial anomalies, causing significant functional and psychological burden to the patients. This study aimed to identify the genetic cause of VWS in a Chinese family. Methods: Whole genome sequencing (WGS) was performed to screen for pathogenic mutations. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Cosegregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics guidelines. Results: A novel frameshift duplication c.373_374dupAA (p.Asn125Lys fs*43) was identified in exon 4 of the interferon regulatory factor 6 (IRF6) gene in all 3 affected members, which were not found in unaffected family members. The novel mutation leads to a frameshift and a premature stop codon which caused putative truncated protein. Protein alignment indicated high evolutionary conservation of the p.N125 residue, and this mutation was predicted by online tools to be damaging and deleterious. Conclusions: This study demonstrates that the novel mutation c.373_374dupAA (p.Asn125Lysfs*43) in the IRF6 gene corresponds to the VWS in this family. The discovery of this pathogenic variant enriches the genotypic spectrum of IRF6 gene and contributes to genetic diagnosis and counseling of families with VWS.

scholarly journals Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene

2001 ◽  
Vol 86 (9) ◽  
pp. 4068-4071 ◽  
Author(s):  
Sorahia Domenice ◽  
Ana Claudia Latronico ◽  
Vinicius Nahime Brito ◽  
Ivo Jorge Prado Arnhold ◽  
Fernando Kok ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Precocious Puberty ◽  
Stop Codon ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Premature Stop Codon ◽  
Rare Condition ◽  
Coding Region ◽  
Primary Adrenal Insufficiency

Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.

Novel Identification of a Four-base-pair Deletion Mutation in PITX2 in a Rieger Syndrome Family

2003 ◽  
Vol 82 (12) ◽  
pp. 1008-1012 ◽  
Author(s):  
Y. Wang ◽  
H. Zhao ◽  
X. Zhang ◽  
H. Feng
Keyword(s):  
Base Pair ◽  
Stop Codon ◽  
Critical Role ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
Loss Of Function ◽  
Rieger Syndrome ◽  
Mutational Screening ◽  
Base Pair Deletion ◽  
Pitx2 Gene

Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis.

A novel homozygous frameshift mutation in the FUCA1 gene causes both severe and mild fucosidosis

2018 ◽  
Vol 71 (9) ◽  
pp. 821-824 ◽  
Author(s):  
Nasrollah Saleh-Gohari ◽  
Kolsoum Saeidi ◽  
Roya Zeighaminejad
Keyword(s):  
Next Generation Sequencing ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Next Generation ◽  
Lysosomal Storage ◽  
Illumina Hiseq ◽  
Almost All ◽  
Generation Sequencing

AimsFucosidosis is a rare autosomal recessive lysosomal storage disorder caused by α-L-fucosidase deficiency as a result of FUCA1 gene mutations. Here, we studied clinical features and the molecular basis of fucosidosis in a family from Iran, including two probands and nine family members.MethodsDNA sample of two probands were screened for gene defects using a next generation sequencing technique. The sequencing processes were performed on an Illumina Hiseq 4000 platform. Sequence reads were analysed using BWA-GATK.ResultsNext generation sequencing revealed a frameshift mutation caused by 2 bp deletion (c.837_838 delTG; p.Cys279) in the FUCA1 gene. The identified mutation was tested in all participants. Homozygous patients had almost all the complications associated with fucosidosis, while heterozygous carriers were unaffected.ConclusionsThe variant c.837_838 delTG; p.Cys279 has not been reported previously and is predicted to be pathogenic due to a premature stop codon.

Sign in / Sign up

Export Citation Format

Share Document