scholarly journals The functional consequence of the pathogenic variant in the inflammasome component NLRP3 as the underlying cause of keratitis fugax hereditaria

2022 ◽  
Vol 100 (S267) ◽  
Author(s):  
Sabita Kawan ◽  
Micheal Backlund ◽  
Annamari Immonen ◽  
Joni Turunen
Keyword(s):  
Pathogenic Variant ◽  
Functional Consequence ◽  
Inflammasome Component

An audit and insights from clinical exome sequencing in psychiatry: genotype-phenotype correlation

2020 ◽  
Author(s):  
Jayant Mahadevan ◽  
Reeteka Sud ◽  
Ravi Kumar Nadella ◽  
Vani P ◽  
Anand G Subramaniam ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Psychiatric Symptoms ◽  
Pathogenic Variant ◽  
Clinical Exome Sequencing ◽  
Mapt Gene ◽  
Nf1 Gene ◽  
Novel Variant ◽  
History Of ◽  
Atypical Presentations ◽  
Minor Physical Anomalies

BACKGROUND:Psychiatric syndromes have polymorphic symptomatology, and are known to be heritable. Psychiatric symptoms (and even syndromes) often occur as part of the clinical presentation in rare Mendelian syndromes. Clinical exome sequencing reports may help with refining diagnosis and influence treatment decisions, in addition to providing a window into the biology of brain and behaviour. We describe a clinical audit of 12 individuals who sought treatment at our hospital, and for whom targeted sequencing was ordered. Three cases are discussed in detail to demonstrate correlations between genotype and phenotype in the clinic.METHODS:Targeted Next-Generation Sequencing (NGS) was done using Clinical Exome Panel (TruSight One, Illumina) covering coding exons and flanking intronic sequences of 4811 genes associated with known inherited diseases. Variants detected were classified according to the American College for Medical Genetics (ACMG) recommendation for standards of interpretation and reporting of sequence variations.RESULTS:Ten out of twelve cases had at least one pathogenic variant. In one of these cases, we detected a known pathogenic variant in MAPT gene in a suspected FTD case, which helped us to confirm the diagnosis. In another case, we detected a novel variant predicted to be deleterious in NF1 gene. Identification of this mutation suggested a change in treatment for the patient, that was of benefit. The same patient also harboured a novel variant in the TRIO gene. This gene may be involved in biological processes that underlie the patient’s psychiatric illness.CONCLUSIONS:The cases discussed here exemplify different scenarios under which targeted exome sequencing can find meaningful application in the clinic: confirming diagnosis (MAPT variant), or modifying treatment (NF1). We suggest that clinical exome sequencing can be a helpful addition to a clinician’s toolkit when there are expediting factors to consider— such as early-onset, strong family history of mental illness, complex/atypical presentations and minor physical anomalies or neurocutaneous markers.

Parietal aplasia and hypophosphatasia in a child harboring a novel mutation in RUNX2 and a likely pathogenic variant in TNSALP

Bone ◽  
2021 ◽  
pp. 115904
Author(s):  
Anna Papadopoulou ◽  
Evangelia Bountouvi ◽  
Vassiliki Sideri ◽  
Paraskevi Moutsatsou ◽  
Nikitas Spyridon Skarakis ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Pathogenic Variant

scholarly journals A Sri Lankan girl with a new genetic variant in the PKLR gene causing pyruvate kinase deficiency: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ahalyaa Sivashangar ◽  
Lallindra Gooneratne ◽  
Barnaby Clark ◽  
David Rees ◽  
Saroj Jayasinghe ◽  
...  
Keyword(s):  
Case Report ◽  
Pyruvate Kinase ◽  
Genetic Variant ◽  
Asian Population ◽  
Pathogenic Variant ◽  
Sri Lankan ◽  
Recessive Trait ◽  
Case Presentation ◽  
Pyruvate Kinase Deficiency ◽  
Hematological Disorders

Abstract Background Erythrocyte pyruvate kinase is expressed under the control of the PKLR gene located on chromosome 1q21. Pyruvate kinase catalyzes the final steps of the glycolytic pathway and creates 50% of the red cell total adenosine triphosphate. Pyruvate kinase deficiency is the commonest glycolytic defect causing congenital non-spherocytic hemolytic anemia inherited in an autosomal recessive trait in which homozygotes and compound heterozygotes are common. Over 200 mutations have been described in patients with pyruvate kinase deficiency. This case report identifies a new pathogenic variant in PKLR gene detected in a patient with severe pyruvate kinase deficiency. Case presentation A Sri Lankan Sinhalese girl who developed neonatal anemia and jaundice within 24 hours of birth with mild hepatomegaly. She was from a nonconsanguineous marriage and had two siblings who had no hematological disorders. She had repeated admissions due to similar illnesses and at the age of 8 years was found to have pyruvate kinase deficiency associated with a novel homozygous pathogenic variant c.507+1delG in the PKLR gene. Conclusions A novel genetic variant in PKLR gene, consistent with pyruvate kinase deficiency, was detected in a Sri Lankan girl. This genetic variant may be specific to the Asian population and requires further studies.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

scholarly journals Ultrasound guided needle biopsy of axilla to evaluate nodal metastasis after preoperative systemic therapy in cohort of 106 breast cancers enriched with BRCA1/2 pathogenic variant carriers

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Baiba Līcīte ◽  
Arvīds Irmejs ◽  
Jeļena Maksimenko ◽  
Pēteris Loža ◽  
Genādijs Trofimovičs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systemic Therapy ◽  
False Positive Rate ◽  
False Negative ◽  
False Negative Rate ◽  
Axillary Node ◽  
Pathogenic Variant ◽  
Axillary Lymph ◽  
Ultrasound Guided ◽  
Node Positive

Abstract Background Aim of the study is to evaluate the role of ultrasound guided fine needle aspiration cytology (FNAC) in the restaging of node positive breast cancer after preoperative systemic therapy (PST). Methods From January 2016 – October 2020 106 node positive stage IIA-IIIC breast cancer cases undergoing PST were included in the study. 18 (17 %) were carriers of pathogenic variant in BRCA1/2. After PST restaging of axilla was performed with ultrasound and FNAC of the marked and/or the most suspicious axillary node. In 72/106 cases axilla conserving surgery and in 34/106 cases axillary lymph node dissection (ALND) was performed. Results False Positive Rate (FPR) of FNAC after PST in whole cohort and BRCA1/2 positive subgroup is 8 and 0 % and False Negative Rate (FNR) – 43 and 18 % respectively. Overall Sensitivity − 55 %, specificity- 93 %, accuracy 70 %. Conclusion FNAC after PST has low FPR and is useful to predict residual axillary disease and to streamline surgical decision making regarding ALND both in BRCA1/2 positive and negative subgroups. FNR is high in overall cohort and FNAC alone are not able to predict ypCR and omission of further axillary surgery. However, FNAC performance in BRCA1/2 positive subgroup is more promising and further research with larger number of cases is necessary to confirm the results.

Two patients from Turkey with a novel variant in the GM2A gene and review of the literature

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Aslı İnci ◽  
Filiz Başak Cengiz Ergin ◽  
Gürsel Biberoğlu ◽  
İlyas Okur ◽  
Fatih Süheyl Ezgü ◽  
...  
Keyword(s):  
Sandhoff Disease ◽  
Pathogenic Variant ◽  
Protein Deficiency ◽  
Gm2 Gangliosidosis ◽  
Infantile Form ◽  
Rare Form ◽  
Inborn Errors ◽  
Activator Protein ◽  
Gm2 Activator ◽  
Gm2 Activator Protein

Abstract Objectives GM2 gangliosidosis is a rare form of inborn errors of metabolism including Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. GM2 activator protein deficiency is an ultra-rare form of GM2 gangliosidosis. To date, 16 cases of GM2 activator protein deficiency have been reported in the literature, and among them, 11 cases were the infantile form of the disease. Here we report the first two patients from Turkey with the infantile form of the disease with a novel likely pathogenic variant. Case presentation A boy of eight months old presented to the metabolic department with very mild neurological deterioration, although he had achieved early developmental milestones at the appropriate time. The parents also had a daughter who had lost skills progressively before one year of age. The boy was evaluated and bilateral cherry-red spots were found with no abnormality in either metabolic screening including β-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant in GM2A was detected in a next-generation sequence panel revealing GM2 activator protein deficiency. His sister was investigated after he was diagnosed with GM2 activator deficiency and it was found that she had the same variant as her brother. Conclusions This case report emphasizes that in the event of normal β-hexosaminidase activity, GM2 activator protein deficiency could be underdiagnosed, and further molecular analysis should be performed. To the best of our knowledge, this boy is one of the youngest patient diagnosed with very mild symptoms. With this novel pathogenic variant, these patients have expanded the mutation spectrum of GM2 activator protein deficiency.

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