scholarly journals Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation

2020 ◽  
Vol 45 (4) ◽  
pp. 603-611
Author(s):  
Peng Fan ◽  
Di Zhang ◽  
Xiao-Cheng Pan ◽  
Kun-Qi  Yang ◽  
Qiong-Yu Zhang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Severe Hypertension ◽  
Chinese Family ◽  
Highly Pathogenic ◽  
Liddle Syndrome ◽  
Serum Potassium Concentration ◽  
Heterozygous Variant ◽  
History Of ◽  
Py Motif ◽  
Monogenic Hypertension

Introduction: Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. Objective: This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. Methods: DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. Results: Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of β-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. Conclusions:We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe 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 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 The association of the Arg1277Gln mutation in the MYH7 gene with myosin storage myopathy in a Chinese family

2020 ◽  
Author(s):  
Li-li Li ◽  
Riu Li ◽  
Dongyun Liu
Keyword(s):  
Muscle Tone ◽  
Cervical Vertebrae ◽  
Chinese Family ◽  
Type I ◽  
Missense Mutations ◽  
Skeletal Muscle Myosin ◽  
Heterozygous Variant ◽  
History Of ◽  
Myosin Storage Myopathy ◽  
The Right

Abstract Background Myosin storage myopathy (MSM) is caused by missense mutations in the MYH7 gene, which encodes the β-cardiac/slow skeletal muscle myosin heavy chain rod (MyHCI). MSM is an autosomal dominant/recessive myopathy characterized by subsarcolemmal accumulations of myosin in type I muscle fibers that results in weakness of the scapula, limb and distal muscles.Methods Here, we report a MSM phenotype that was present across three generations of individuals from the same family, one of whom was a neonate.Results At birth, the neonate had an elevated creatine kinase level and decreased muscle tone in the limbs. At 2 months of age, the infant’s cervical vertebrae caused his head to be skewed to the right. At 7 months of age, the infant’s development was delayed.Whole exome sequencing showed a novel heterozygous variant NM_000257.3: c.3830G>A (p.Arg1277Gln) at exon 28 of the MYH7 gene in the DNA of the infant and his father.Conclusions Previously, which site has only been reported in 2 cases of cardiomyopathy; therefore, this study expands our knowledge of the clinical phenotypes associated with mutations within the rod region of MyHCI. Importantly, close follow-up of the neonate will provide important information on the natural history of MSM associated with MYH7 gene mutation.

scholarly journals Liddle syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of SCNN1B

2018 ◽  
Vol 7 (12) ◽  
pp. 1528-1534
Author(s):  
Peng Fan ◽  
Chao-Xia Lu ◽  
Di Zhang ◽  
Kun-Qi Yang ◽  
Pei-Pei Lu ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Early Onset ◽  
Frameshift Mutation ◽  
Heterozygous Mutation ◽  
Autosomal Dominant Disorder ◽  
Liddle Syndrome ◽  
Py Motif ◽  
Monogenic Hypertension ◽  
Generation Sequencing ◽  
Epithelial Sodium Channel Enac

Liddle syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.

scholarly journals National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer

2017 ◽  
Vol 35 (34) ◽  
pp. 3800-3806 ◽  
Author(s):  
Christopher P. Childers ◽  
Kimberly K. Childers ◽  
Melinda Maggard-Gibbons ◽  
James Macinko
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Unmet Need ◽  
Cancer Control ◽  
The United States ◽  
Eligibility Criteria ◽  
Cross Sectional ◽  
Age Of Diagnosis ◽  
History Of ◽  
Interview Survey

Purpose In the United States, 3.8 million women have a history of breast (BC) or ovarian cancer (OC). Up to 15% of cases are attributable to heritable mutations, which, if identified, provide critical knowledge for treatment and preventive care. It is unknown how many patients who are at high risk for these mutations have not been tested and how rates vary by risk criteria. Methods We used pooled cross-sectional data from three Cancer Control Modules (2005, 2010, 2015) of the National Health Interview Survey, a national in-person household interview survey. Eligible patients were adult females with a history of BC and/or OC meeting select 2017 National Comprehensive Cancer Network eligibility criteria on the basis of age of diagnosis and family history. Outcomes included the proportion of individuals reporting a history of discussing genetic testing with a health professional, being advised to undergo genetic testing, or undergoing genetic testing for BC or OC. Results Of 47,218 women, 2.7% had a BC history and 0.4% had an OC history. For BC, 35.6% met one or more select eligibility criteria; of those, 29.0% discussed, 20.2% were advised to undergo, and 15.3% underwent genetic testing. Testing rates for individual eligibility criteria ranged from 6.2% (relative with OC) to 18.2% (diagnosis ≤ 45 years of age). For OC, 15.1% discussed, 13.1% were advised to undergo, and 10.5% underwent testing. Using only four BC eligibility criteria and all patients with OC, an estimated 1.2 to 1.3 million individuals failed to receive testing. Conclusion Fewer than one in five individuals with a history of BC or OC meeting select National Cancer Comprehensive Network criteria have undergone genetic testing. Most have never discussed testing with a health care provider. Large national efforts are warranted to address this unmet need.

scholarly journals R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

2021 ◽  
pp. 123-130
Author(s):  
Anker Stubberud ◽  
Emer O’Connor ◽  
Erling Tronvik ◽  
Henry Houlden ◽  
Manjit Matharu
Keyword(s):  
Mental Retardation ◽  
Case Report ◽  
Genetic Testing ◽  
Head Trauma ◽  
Cerebral Oedema ◽  
De Novo ◽  
Minor Head Trauma ◽  
Hemiplegic Migraine ◽  
Wide Range ◽  
History Of

Mutations in the <i>CACNA1A</i> gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the <i>CACNA1A</i> gene (c.4055G&#x3e;A, p.R1352Q). The R1352Q <i>CACNA1A</i> variant shares the phenotype with other described <i>CACNA1A</i> mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

scholarly journals Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

2021 ◽  
Vol 22 (9) ◽  
pp. 4700
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Giuseppe Ciconte ◽  
Ilaria Rivolta ◽  
Valeria Borrelli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Brugada Syndrome ◽  
Electrophysiological Study ◽  
Functional Characterization ◽  
The Family ◽  
Novel Variant ◽  
History Of ◽  
Scn5a Gene

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

scholarly journals Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

2021 ◽  
Vol 22 (14) ◽  
pp. 7292
Author(s):  
Luca Marsili ◽  
Jennifer Sharma ◽  
Alberto J. Espay ◽  
Alice Migazzi ◽  
Elhusseini Abdelghany ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia Type ◽  
Niemann Pick Disease ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
History Of ◽  
Ataxia Syndrome ◽  
Niemann Pick

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

BRCA1/2 Genetic Testing in the Community Setting

2002 ◽  
Vol 20 (22) ◽  
pp. 4485-4492 ◽  
Author(s):  
Wendy Y. Chen ◽  
Judy E. Garber ◽  
Suzanne Higham ◽  
Katherine A. Schneider ◽  
Katie B. Davis ◽  
...  
Keyword(s):  
United States ◽  
Ovarian Cancer ◽  
Genetic Testing ◽  
Cancer Prevention ◽  
Community Setting ◽  
The United States ◽  
Care Providers ◽  
Prevention Strategies ◽  
History Of ◽  
Genetic Results

PURPOSE: BRCA1/2 genetic testing has been commercially available in the United States since 1996. Most published reports described BRCA1/2 testing as research studies at large academic centers, but less is known about testing in the community. This study evaluates the process and early outcomes of BRCA1/2 genetic testing as a clinical service in the community setting. METHODS: Surveys were mailed to women in the United States whose health care providers ordered BRCA1/2 genetic testing from Myriad Genetic Laboratories from August 1998 through July 2000. Women tested at 149 large academic centers were excluded. Main outcome measures were demographic characteristics, recall of and satisfaction with the genetic testing process, and likelihood of pursuing cancer prevention strategies. RESULTS: Among the 646 respondents, 414 (64%) had a personal history of cancer and 505 (78%) had at least one first-degree relative with breast and/or ovarian cancer. Most subjects (82%) recalled discussions of informed consent before testing (median time, 30 minutes). Genetic results were conveyed during an office visit (57%), by telephone (39%), or by mail (3%). More than 75% of respondents were “very satisfied with the counseling received.” Cancer-free subjects with a germline mutation were more likely to consider prevention strategies after receiving the genetic results. CONCLUSION: Virtually all respondents had a personal and/or family history of breast/ovarian cancer. Although pretest and posttest communications were not standardized, overall satisfaction with clinical breast cancer genetic testing was high. Additional follow-up will provide data on future cancer prevention practices and cancer incidence.

scholarly journals Serial Observations and Mutational Analysis of an Adoptee with Family History of Hypertrophic Cardiomyopathy

2010 ◽  
Vol 2010 ◽  
pp. 1-4
Author(s):  
Bronwyn Harris ◽  
Jean P. Pfotenhauer ◽  
Cheri A. Silverstein ◽  
Larry W. Markham ◽  
Kim Schafer ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Family History ◽  
Mutational Analysis ◽  
Clinical Findings ◽  
Dominant Mode ◽  
Natural Mother ◽  
History Of ◽  
In Cis ◽  
Inherited Cardiac Disease

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variantsin cismay be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.

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