scholarly journals Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

2021 ◽  
Vol 22 (7) ◽  
pp. 3786
Author(s):  
Andreas Brodehl ◽  
Alexey Meshkov ◽  
Roman Myasnikov ◽  
Anna Kiseleva ◽  
Olga Kulikova ◽  
...  
Keyword(s):  
Medical History ◽  
Splice Site Mutation ◽  
Pathogenic Mutation ◽  
Large Deletion ◽  
Loss Of Function ◽  
Arrhythmogenic Cardiomyopathy ◽  
Site Mutation ◽  
Snp Arrays ◽  
Number Of Patients ◽  
History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

scholarly journals AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer

2019 ◽  
Vol 24 (1) ◽  
pp. 28-32
Author(s):  
Youssef Elhaji ◽  
Cherise Hedlin ◽  
Anu Nath ◽  
Emma L. Price ◽  
Christopher Gallant ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Index Case ◽  
Pcr Amplification ◽  
Splice Site Mutation ◽  
Loss Of Function ◽  
Palmoplantar Keratoderma ◽  
Site Mutation ◽  
Pcr Products ◽  
History Of

Background: Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles. PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations. It has been suggested that PPPK1 may be associated with an increased predisposition to systemic malignancies. Objectives: To evaluate the presence of AAGAB mutations in Canadian families with PPPK1 and the possible increased predisposition to systemic malignancies. Methods: Eighteen unrelated Canadian families with PPPK1 were recruited for this study. Genomic DNA was extracted from saliva and PCR amplification was performed for all AAGAB exons and exon/intron junctions. PCR products were sequenced and analyzed for mutations. A family history of malignancy was obtained from the index case and, when possible, from other family members. Results: We have identified 5 heterozygous AAGAB loss of function mutations in 11 families. The mutation c.370 C>T, p.Arg124* was the most prevalent and was identified in 6 families. A splice site mutation, c.451+3delAAGT, was identified in 2 families. The other mutations c.473delG, p.Gly158Glufs*0; c.550-551insAAT, p.Gly183*; and c.505-506 dupAA, p.Asn169Lysfs*6 were each identified in 1 family. Different cancers were reported in 11 families (Table 1 and Supplemental Figure S1). Conclusions: AAGAB mutations were found in 11 of 18 families with PPPK1. In some families there appears to be an association with cancer.

Safety and Efficacy of Various Intravenous Insulin Infusion Rates in Patients With and Without Diabetes Presenting With Hypertriglyceridemia

2022 ◽  
pp. 106002802110701
Author(s):  
Francisco Ibarra ◽  
Kaitlyn Loi ◽  
Ann W. Vu
Keyword(s):  
Medical History ◽  
Insulin Infusion ◽  
Case Reports ◽  
Retrospective Chart Review ◽  
Acute Management ◽  
Past Medical History ◽  
Safety And Efficacy ◽  
Intravenous Insulin ◽  
Number Of Patients ◽  
History Of

Background The use of IV insulin infusions in the acute management of hypertriglyceridemia has only been evaluated in small observational studies and case reports. Objective To evaluate the safety and efficacy of IV insulin infusions in the acute management of hypertriglyceridemia. Methods This was a retrospective chart review of adult patients who received an IV insulin infusion for the acute management of hypertriglyceridemia. The primary efficacy and safety outcomes were the number of patients who achieved a triglyceride level <500 mg/dL and experienced hypoglycemia (<70 mg/dL), respectively. A subgroup analysis was performed to compare outcomes between patients with and without diabetes, in addition to the IV insulin infusion rate received. Results In the total population (n = 51), there were no statistically significant differences between the insulin intensity groups in the number of patients who achieved TG levels <500 mg/dL. Compared to patients with a past medical history of diabetes, more patients without a past medical history of diabetes achieved triglyceride levels <500 mg/dL (14% vs 53%, respectively, P < 0.001). The number of hypoglycemic events observed in patients with and without a past medical history of diabetes were 5 (14%) and 4 (27%), respectively ( P = 0.023). Conclusion and Relevance Our findings suggest that patients who present with lower initial TG levels are more likely to achieve TG levels <500 mg/dL. To minimize the risk of hypoglycemia providers should consider prescribing a concomitant dextrose infusion and limiting IV insulin infusion rates ≤ 0.075 units/kg/h.

scholarly journals ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Marie F. Smeland ◽  
Conor McClenaghan ◽  
Helen I. Roessler ◽  
Sanne Savelberg ◽  
Geir Åsmund Myge Hansen ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Cardiac Dysfunction ◽  
Systolic Dysfunction ◽  
Splice Site Mutation ◽  
Cerebral White Matter ◽  
Sulfonylurea Receptor ◽  
Loss Of Function ◽  
Mild Intellectual Disability ◽  
Site Mutation ◽  
Gain Of Function

Abstract Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

Arrhythmogenic Right Ventricular Cardiomyopathy with Left Ventricular Involvement: A Novel Splice Site Mutation in the DSG2 Gene

Cardiology ◽  
2015 ◽  
Vol 130 (3) ◽  
pp. 159-161 ◽  
Author(s):  
Marina Pereira Fernandes ◽  
Olga Azevedo ◽  
Vitor Pereira ◽  
Lucy Calvo ◽  
António Lourenço
Keyword(s):  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Splice Site Mutation ◽  
Left Ventricular ◽  
Transthoracic Echocardiogram ◽  
Ventricular Cardiomyopathy ◽  
Site Mutation ◽  
Electrocardiographic Monitoring ◽  
History Of ◽  
The Right

We report the case of a 37-year-old male patient admitted to the cardiac intensive care unit for acute pulmonary edema. He had a history of excessive alcoholic consumption and had had a viral syndrome in the preceding 10 days. A transthoracic echocardiogram revealed severe biventricular dysfunction, mild dilatation of the left heart chambers, and severe dilatation of the right chambers. Nonsustained ventricular tachycardia with a left bundle branch block morphology was detected during electrocardiographic monitoring. In the follow-up, he underwent a contrast-enhanced transthoracic echocardiogram and a cardiac resonance which were compatible with the diagnosis of arrhythmogenic right ventricular cardiomyopathy with biventricular involvement. Molecular analysis detected the mutation c.1423+2T>G (IVS10 ds +2T>G) in intron 10 of the gene DSG2 (desmoglein-2) in heterozygosity. To our knowledge, this mutation has not been previously described in arrhythmogenic right ventricular cardiomyopathy.

scholarly journals Somatic mosaicism and compound heterozygosity in female hemophilia B

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1585-1587 ◽  
Author(s):  
Jean-Marc Costa ◽  
Dominique Vidaud ◽  
Ingrid Laurendeau ◽  
Michel Vidaud ◽  
Edith Fressinaud ◽  
...  
Keyword(s):  
Splice Site ◽  
Somatic Mosaicism ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Hemorrhagic Diathesis ◽  
Site Mutation ◽  
History Of ◽  
Sporadic Cases ◽  
In Trans

Abstract Sequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5′ splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling.

Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers

2020 ◽  
Vol 33 (10) ◽  
pp. 1353-1358
Author(s):  
Ayla Güven ◽  
Martin Konrad ◽  
Karl P. Schlingmann
Keyword(s):  
Vitamin D ◽  
Stop Codon ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Loss Of Function ◽  
Site Mutation ◽  
Medullary Nephrocalcinosis ◽  
Idiopathic Infantile Hypercalcemia

AbstractObjectivesBoth CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today.Case presentationHypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis.ConclusionsA biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.

scholarly journals Somatic mosaicism and compound heterozygosity in female hemophilia B

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1585-1587
Author(s):  
Jean-Marc Costa ◽  
Dominique Vidaud ◽  
Ingrid Laurendeau ◽  
Michel Vidaud ◽  
Edith Fressinaud ◽  
...  
Keyword(s):  
Splice Site ◽  
Somatic Mosaicism ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Hemorrhagic Diathesis ◽  
Site Mutation ◽  
History Of ◽  
Sporadic Cases ◽  
In Trans

Sequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5′ splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling.

scholarly journals Clinical picture of influenza caused by a different virus serotypes

2015 ◽  
Vol 20 (6) ◽  
pp. 39-43
Author(s):  
A. F Popov ◽  
A. I Simakova ◽  
K. A Dmitrenko ◽  
I. V Zenin
Keyword(s):  
Medical History ◽  
Clinical Picture ◽  
Influenza A ◽  
Seasonal Influenza ◽  
High Rate ◽  
Influenza B ◽  
Number Of Patients ◽  
Influenza A H1n1 ◽  
History Of ◽  
Complications And Mortality

There was analyzed the medical history of 561 patients with influenza during the period of 2009-2014, Influenza A (H1N1) pdm09 was diagnosed in 261 cases, accounting for 46.5% of the total number of patients; Influenza A (H1N1) - in 148 cases (26.4%); Influenza A (H3N2) - in 102 cases (18.2%); Influenza B - in 50 cases (8.9%). The clinical picture of influenza A (H1N1) pdm09 differed from seasonal influenza A (H1N1), A (H3N2), and B by more severe course, the high rate of complications and mortality.

scholarly journals Delayed diagnosis of X-linked agammaglobulinaemia in a boy with recurrent meningitis

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ya-Ni Zhang ◽  
Yuan-Yuan Gao ◽  
Si-Da Yang ◽  
Bin-Bin Cao ◽  
Ke-Lu Zheng ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Delayed Diagnosis ◽  
Splice Site Mutation ◽  
Peripheral Blood Lymphocytes ◽  
Immunoglobulin M ◽  
Heterozygous Mutation ◽  
Developmental Defect ◽  
Recurrent Meningitis ◽  
Site Mutation ◽  
Number Of Patients

Abstract Background X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton’s tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. Case report An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein. Conclusion Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.

Sign in / Sign up

Export Citation Format

Share Document