scholarly journals Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser))

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1034
Author(s):  
Gaetano Pietro Bulfamante ◽  
Laura Carpenito ◽  
Emma Bragantini ◽  
Silvia Graziani ◽  
Maria Bellizzi ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Arterial Calcification ◽  
Medium Size ◽  
Internal Elastic Lamina ◽  
Pathogenic Variants ◽  
Abcc6 Gene ◽  
Enpp1 Gene

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

scholarly journals Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1895
Author(s):  
Max Jonathan Stumpf ◽  
Nadjib Schahab ◽  
Georg Nickenig ◽  
Dirk Skowasch ◽  
Christian Alexander Schaefer
Keyword(s):  
Current Knowledge ◽  
Treatment Options ◽  
Pseudoxanthoma Elasticum ◽  
Skin Lesions ◽  
Arterial Calcification ◽  
Future Perspectives ◽  
Strong Inhibitor ◽  
New Therapeutic Approaches ◽  
Pathogenic Variants ◽  
Abcc6 Gene

Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease with an estimated prevalence of between 1 per 25,000 and 56,000. Its main hallmarks are characteristic skin lesions, development of choroidal neovascularization, and early-onset arterial calcification accompanied by a severe reduction in quality-of-life. Underlying the pathology are recessively transmitted pathogenic variants of the ABCC6 gene, which results in a deficiency of ABCC6 protein. This results in reduced levels of peripheral pyrophosphate, a strong inhibitor of peripheral calcification, but also dysregulation of blood lipids. Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them. In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and development, and future perspectives.

scholarly journals CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2

2021 ◽  
Vol 22 (22) ◽  
pp. 12423
Author(s):  
Sara Morais ◽  
Mónica Pereira ◽  
Catarina Lau ◽  
Ana Gonçalves ◽  
Catarina Monteiro ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Nucleotide Exchange ◽  
Pathogenic Variants ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Heterozygous Carriers

RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recessive platelet function disease. We report on the clinical manifestations and laboratory features of a Portuguese family with a likely pathogenic variant in RASGRP2 (c.999G>C leading to a p.Lys333Asn change in the CDC25 catalytic domain of CalDAG-GEFI) and discuss the contribution of this variant to the disease manifestations. Based on the study of this family with one homozygous patient and five heterozygous carriers and on a critical analysis of the literature, we challenge previous knowledge that CalDAG-GEFI deficiency only manifests in homozygous patients. Our data suggest that at least for the RASGRP2 variant reported herein, there is a phenotypic expression, albeit milder, in heterozygous carriers.

scholarly journals Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families

2019 ◽  
Vol 28 (2) ◽  
pp. 244-252 ◽  
Author(s):  
Yanqin Zhang ◽  
Jie Ding ◽  
Suxia Wang ◽  
Hongwen Zhang ◽  
Xuhui Zhong ◽  
...  
Keyword(s):  
Alport Syndrome ◽  
Urine Analysis ◽  
Family Members ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
The Other ◽  
Normal Result ◽  
Chinese Families ◽  
Col4a5 Gene ◽  
Pathogenic Variants

Abstract X-linked Alport syndrome (XLAS) is an inherited renal disease caused by mutations in COL4A5 gene. The c.2858G>T(p.(G953V)) in COL4A5 gene (rs78972735) has been considered pathogenic previously. However, there are conflicting interpretations of its pathogenicity recently. Here we presented 19 Chinese families, out of which 36 individuals (18 probands and 18 family members) carried the c.2858G>T(p.(G953V)) in COL4A5 gene. The clinical manifestations and genetic findings of them were analyzed. We found there were no clinical features of Alport syndrome not only in six probands with c.2858G>T(p.(G953V)) in COL4A5 plus pathogenic variants in other genes (e.g., WT1, ADCK4, NPHP1, TRPC6, COL4A4, and PAX2) but also in another six probands with only the c.2858G>T(p.(G953V)) variant. The other six probands with a combination of c.2858G>T(p.(G953V)) and another pathogenic variant in COL4A5 had XLAS. Eleven family members (11/18, nine females and two males) who had only the c.2858G>T(p.(G953V)) variant were asymptomatic. These two males (at age of 42 and 35 years) had normal result of urine analysis and no more clinical traits of Alport syndrome. We conclude c.2858G>T(p.(G953V)) in COL4A5 gene is not a pathogenic variant for XLAS. Individuals should not be diagnosed as XLAS only based on the detection of c.2858G>T(p.(G953V)) in COL4A5 gene.

VWF antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene

Blood ◽  
2021 ◽  
Author(s):  
Brooke Sadler ◽  
Pamela Christopherson ◽  
Gabe Haller ◽  
Robert R Montgomery ◽  
Jorge Di Paola ◽  
...  
Keyword(s):  
Rare Variants ◽  
Normal Subjects ◽  
Pathogenic Variant ◽  
Von Willebrand Disease ◽  
Pathogenic Variants ◽  
Coding Variants ◽  
Von Willebrand ◽  
The Impact ◽  
Generation Sequencing

Approximately 35% of patients with Type 1 von Willebrand Disease (VWD) do not have a known pathogenic variant in the VWF gene. We aimed to understand the impact of coding variants in VWF on VWD risk and VWF antigen (VWF:Ag) levels. 527 Low VWF and VWD patients and 210 healthy controls were studied. VWF sequencing was performed and VWF:Ag levels assayed. CADD (Combined Annotation Dependent Depletion) score >20 was used as a measure of predicted pathogenicity. The number of rare nonsynonymous VWF variants significantly predicted VWF:Ag levels (p=1.62x10-21). There was an association between average number of rare nonsynonymous VWF variants with VWD Type 1 (p=2.4x10-13) and Low VWF (p=1.6x10-27) compared to normal subjects, with Type 1 subjects possessing on average >2 times as many rare variants as those with Low VWF and eight times as many as normal subjects. The number of rare nonsynonymous variants significantly predicts VWF:Ag levels even after controlling for presence of a variant with CADD score > 20 or a known pathogenic variant in VWF (p=2.7x10-14). The number of rare nonsynonymous variants in VWF as well as the presence of a variant with CADD >20 are both significantly associated with VWF levels. The association with rare nonsynonymous variants holds even when controlling for known pathogenic variants, suggesting that additional variants, both in VWF or elsewhere, are also associated with VWF:Ag levels. Patients with higher VWF:Ag levels who have fewer rare nonsynonymous variants in the VWF gene could benefit from next-generation sequencing to find the cause of their bleeding.

scholarly journals A 2-Year-Old Child with Bilateral Ectopis Lentis and a Novel FBN1 Gene Variant Cys129Ser

2017 ◽  
Vol 07 (02) ◽  
pp. 083-085 ◽  
Author(s):  
Ahmed Mohammad ◽  
Paldeep Atwal
Keyword(s):  
Genetic Analysis ◽  
Marfan Syndrome ◽  
Pathogenic Variant ◽  
Gene Variant ◽  
Ectopia Lentis ◽  
Fbn1 Gene ◽  
Pathogenic Variants ◽  
Syndrome Diagnosis ◽  
History Of

AbstractMarfan syndrome and dominant ectopia lentis are part of type 1 fibrillinopathies that are caused by FBN1 pathogenic variants. Making a diagnosis could be challenging due to the clinical overlap between these disorders. The revised Ghent criteria used for Marfan syndrome diagnosis helped in resolving some of the confusion, especially in younger children. We report on a case of bilateral ectopia lentis in a 2-year-old child with a normal echocardiogram. FBN1 sequencing revealed a novel likely pathogenic variant described as c.385T > A (p.Cys129Ser). The patient's father also has a history of bilateral ectopia lentis and his genetic analysis detected the same FBN1 variant as the proband.

Monogenic Diabetes: Genetics and Relevance on Diabetes Mellitus Personalized Medicine

2020 ◽  
Vol 16 (8) ◽  
pp. 807-819 ◽  
Author(s):  
Madalena Sousa ◽  
Jácome Bruges-Armas
Keyword(s):  
Diabetes Mellitus ◽  
Complex Disease ◽  
Clinical Manifestations ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Diabetes Genetics ◽  
Individualize Treatment

Background: Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. Methods: Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. Results: The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. Discussion: Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. Conclusion: Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.

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 Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1218
Author(s):  
Raffaella Brunetti-Pierri ◽  
Marianthi Karali ◽  
Francesco Testa ◽  
Gerarda Cappuccio ◽  
Maria Elena Onore ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Joubert Syndrome ◽  
Male Adult ◽  
Full Field ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Male Individual ◽  
The Central Nervous System

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the ‘molar tooth sign’ and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

scholarly journals Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants

2020 ◽  
Vol 9 (2) ◽  
pp. 545 ◽  
Author(s):  
Rob W. Roudijk ◽  
Laurens P. Bosman ◽  
Jeroen F. van der Heijden ◽  
Jacques M. T. de Bakker ◽  
Richard N. W. Hauer ◽  
...  
Keyword(s):  
Early Stage ◽  
Pathogenic Variant ◽  
Observer Agreement ◽  
Arrhythmogenic Cardiomyopathy ◽  
Fragmented Qrs ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Disease Penetrance ◽  
Ecg Leads ◽  
And Control

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) (p < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited.

scholarly journals Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1879
Author(s):  
Marcello Scala ◽  
Irene Schiavetti ◽  
Francesca Madia ◽  
Cristina Chelleri ◽  
Gianluca Piccolo ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Multivariate Statistical ◽  
Gene Deletions ◽  
Pathogenic Variants ◽  
Lisch Nodules ◽  
Next Generation Sequencing Ngs

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

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