scholarly journals New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly

2021 ◽  
pp. 1-15
Author(s):  
Viviane Freitas de Castro ◽  
Daniel Mattos ◽  
Flavia Martinez de Carvalho ◽  
Denise Pontes Cavalcanti ◽  
Milagros M. Duenas-Roque ◽  
...  
Keyword(s):  
Latin American ◽  
Sanger Sequencing ◽  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Driver Gene ◽  
Incomplete Penetrance ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Facial Defects ◽  
Domain Conservation

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the <i>SHH</i>, <i>SIX3</i>, <i>ZIC2</i>, and <i>TGIF1</i> genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new <i>SHH</i> variants and a third known <i>SIX3</i> likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with <i>SHH</i> pathogenic variants, presented benign variants of the <i>SHH</i>, <i>SIX3</i>, <i>ZIC2</i>, and <i>TGIF1</i> genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same <i>SIX3</i> variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.

scholarly journals A CASE OF RARE INHERITED RESTRICTIVE CARDIOMYOPATHY CAUSED BY A NOVEL MUTATION IN MYH7 GENE

2021 ◽  
Vol 9 (09) ◽  
pp. 780-786
Author(s):  
Aya Belkhadir ◽  
◽  
Kamal Marzouki ◽  
Mohamed Aoudad ◽  
Amale Tazi Mezalek ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Gene Mutations ◽  
Restrictive Cardiomyopathy ◽  
Incomplete Penetrance ◽  
Patients At Risk ◽  
History Of ◽  
Pace Maker

Introduction: Inherited restrictive cardiomyopathy (RCM) is a rare cause of RCM associated with cytoskeletal and sarcoma gene mutations. We describe a case of inherited RCM due to MYH7s genetic mutation.Case description: A 66 year-old-woman was admitted for acute global heart failure. She had a family history of RCM with a mutation of MYH7 gene: sons sudden death at 30, one of her daughters who is 40 and grandson who is 1. The transthoracic cardiac ultrasound (TTE) showed a bi-atrial dilation, a non-dilated left ventricle (LV) non-hypertrophied. Genetic investigation found the same pathogenic missense mutation (c. 1477A>G in heterozygous state) in our patient and her daughter who has a non-obstructive hypertrophy cardiomyopathy (HCM).A few weeks later, our patient had a syncope on complete atrioventricular block. A triple chamber pace maker was installed. Discussion: Familial RCMs mutations are characterized by high allelic, genetic and phenotypic variability, with autosomal dominant inheritance and variable penetrance. This mutation is rarely found in RCM, it is usually reported in HCM (OMIM 160760). Genetic screening should be considered to identify patients at risk in families with suspected familial transmission. MYH7 mutations seem to be associated with severe phenotypes, earlier age of onset and more pejorative evolution than other mutations. Conclusion:The evaluation of familial RCM requires an understanding of its variable phenotypic expression and incomplete penetrance. RCM and HCM may coexist in the same family. Genetic testing for hereditary RCM should be considered when secondary causes have been excluded.

A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism

2019 ◽  
Vol 92 (1) ◽  
pp. 56-63
Author(s):  
Naomi Hatabu ◽  
Naho Katori ◽  
Takeshi Sato ◽  
Naonori Maeda ◽  
Eri Suzuki ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Phenotypic Variability ◽  
Early Adulthood ◽  
Familial Case ◽  
Incomplete Penetrance ◽  
Heterozygous Deletion ◽  
Imaging Studies ◽  
Intact Pth ◽  
Pathogenic Variants ◽  
Pth Level

Introduction: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT. Case Description: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the “second hit.” Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history. Conclusions: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.

Coinheritance of 2 New Potentially Damaging Heterozygous COL7A1 Variants in a Family With Autosomal Dominant Epidermolysis Bullosa Pruriginosa

2018 ◽  
Vol 21 (6) ◽  
pp. 580-584
Author(s):  
Gordon I Hale ◽  
Marta C Cohen ◽  
Oliver W Quarrell ◽  
John A McGrath ◽  
Andrew G Messenger
Keyword(s):  
Epidermolysis Bullosa ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Phenotypic Variability ◽  
Incomplete Penetrance ◽  
Histopathological Diagnosis ◽  
Delayed Presentation ◽  
Pathogenic Variants ◽  
Type Vii Collagen ◽  
Phenotypic And Genotypic Variability

Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of EB which is characterized by intense pruritus with blistering and nodular or lichenoid lesions most prominent on the lower extremities. It is caused by variants in COL7A1 which encodes for type VII collagen. There is wide phenotypic and genotypic variability between affected individuals. We report 2 potentially pathogenic variants in COL7A1 occurring on the same allele in a family with EBP and autosomal dominant inheritance. Late-onset EBP and incomplete penetrance may lead to delayed presentation in affected family members with the same variants. The broad phenotypic variability seen in EBP suggests that further genotypic and environmental factors may influence presentation. Genetic and histopathological diagnosis is essential, given the considerable overlap with clinically similar presentations such as hypertrophic lichen planus.

scholarly journals Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4014
Author(s):  
Masato Yonamine ◽  
Koichiro Wasano ◽  
Yuichi Aita ◽  
Takehito Sugasawa ◽  
Katsutoshi Takahashi ◽  
...  
Keyword(s):  
Ethnic Differences ◽  
Sanger Sequencing ◽  
Clinical Decision Making ◽  
Japanese Patients ◽  
Clinical Decision ◽  
Phenotype Correlation ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Japanese Cohort ◽  
High Incidence

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype–phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

scholarly journals The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?

2020 ◽  
Vol 21 (17) ◽  
pp. 6434
Author(s):  
Maria Bueno Marinas ◽  
Rudy Celeghin ◽  
Marco Cason ◽  
Gaetano Thiene ◽  
Cristina Basso ◽  
...  
Keyword(s):  
Gene Expression Regulation ◽  
Phenotypic Variability ◽  
Incomplete Penetrance ◽  
Primary Role ◽  
Arrhythmogenic Cardiomyopathy ◽  
Small Noncoding Rnas ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Fatty Replacement ◽  
Genes Encoding

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for desmosomal proteins. AC incomplete penetrance and phenotypic variability advocate that other factors than genetics may modulate the disease, such as microRNAs (miRNAs). MiRNAs are small noncoding RNAs with a primary role in gene expression regulation and network of cellular processes. The implication of miRNAs in AC pathogenesis and their role as biomarkers for early disease detection or differential diagnosis has been the objective of multiple studies employing diverse designs and methodologies to detect miRNAs and measure their expression levels. Here we summarize experiments, evidence, and flaws of the different studies and hitherto knowledge of the implication of miRNAs in AC pathogenesis and diagnosis.

scholarly journals Expanding the genetic spectrum of TUBB1-related thrombocytopenia

2021 ◽  
Author(s):  
Verónica Palma-Barqueros ◽  
Loredana Bury ◽  
Shinji Kunishima ◽  
Maria L Lozano ◽  
Agustin Rodriguez Alen ◽  
...  
Keyword(s):  
Phenotypic Expression ◽  
Incomplete Penetrance ◽  
Peripheral Blood Cd34 ◽  
Pathogenic Variants ◽  
Clinical Investigations ◽  
Microtubular Network ◽  
Proplatelet Formation ◽  
Insight Into ◽  
Platelet Shape

β1-tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying six β1-tubulin variants: p.Cys12Leufs12*, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size and a minority no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant, displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets, while had negligible effect on platelet activation, secretion or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.

scholarly journals Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Elham Alehabib ◽  
Zahra Esmaeilizadeh ◽  
Sakineh Ranji-Burachaloo ◽  
Abbas Tafakhori ◽  
Hossein Darvish ◽  
...  
Keyword(s):  
Brain Imaging ◽  
Neurodevelopmental Disorders ◽  
Age At Onset ◽  
Incomplete Penetrance ◽  
Molecular Heterogeneity ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
Wide Range ◽  
Epileptic Patients

Abstract Background Epilepsy is a neurological disorder characterized by the potential to induce seizure and accompanied by cognitive, psychological, and social consequences. CACNA1A gene is a voltage-gated P/Q-type Cav2.1 channel that is broadly expressed in the central nervous system, and the pathogenic variants within this gene may be associated with the epileptic phenotype. In the present study, we collected clinical and molecular data related to epileptic patients with CACNA1A pathogenic variants and investigated possible meaningful relationship between age at onset, neurodevelopmental disorders, type of seizures, brain imaging abnormalities, genotype, and protein domains. Results In our retrospective literature studies, from among 890 articles reviewed, a total of 90 individuals were related to epilepsy phenotype. Our findings showed that about 90 percent of patients have shown the first symptoms in childhood and teenage years and different types of neurodevelopmental disorders, such as intellectual disability, developmental arrest, and behavioral disorders, have been common findings for these patients. Further, a wide range of abnormalities have been observed in their brain imaging, and generalized seizures have been the most type of seizures in these patients. However, our data showed no specific genotype–phenotype correlation in epileptic patients with CACNA1A pathogenic alterations. Conclusions Our study focused on epileptic phenotype in patients with CACNA1A pathogenic variants and showed a wide range of clinical and molecular heterogeneity with no specific genotype–phenotype correlation. It seems that incomplete penetrance, de-novo variants, and modifier genes are obstacles in predicting the clinical outcome.

scholarly journals KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants

2021 ◽  
Author(s):  
Claudia Ricci ◽  
Alfonso Cerase ◽  
Giulia Riolo ◽  
Giuditta Manasse ◽  
Stefania Battistini
Keyword(s):  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Premature Stop Codon ◽  
De Novo Mutation ◽  
Incomplete Penetrance ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Mutation Carriers ◽  
Familial Form ◽  
Sporadic Cases

AbstractCerebral cavernous malformations (CCMs) are vascular malformations that may result in headaches, seizures, focal neurological deficits, and hemorrhage. CCMs occur sporadically (80%) or in familial form (20%), with autosomal dominant inheritance. Among the three CCM-related genes, mutations in KRIT1 account for 53–65% of familial cases and more than 100 different mutations have been identified so far. In the present work, we describe the clinical, neuroradiological, and genetic findings of sixteen CCM Italian patients, 13 belonging to 4 unrelated families and 3 sporadic cases. Six distinct KRIT1 gene variants, two novel (c.1730+1_1730+3del, c.1664 C>T) and four previously described (c.966G>A, c.1255-1G>A c.1197_1200del, c.1255-1_1256del), were identified, including a possible de novo mutation. All the variants resulted in a premature stop codon. Cerebral 1.5 T magnetic resonance imaging showed multiple CCMs in all the mutation carriers for whom it was available, including sporadic cases. One patient had also cutaneous angiomas. Among the mutation carriers, symptomatic patients constituted 66% and a variable phenotypic expression was observed. Our data confirms phenotypic variability and incomplete penetrance of neurological symptoms in KRIT1-positive families, expands the mutational spectrum of this gene, and highlights how sporadic cases with multiple lesions need an approach similar to individuals with familial CCM.

scholarly journals Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

2021 ◽  
Vol 11 (3) ◽  
pp. 122-128
Author(s):  
Priya Bhardwaj ◽  
Christoffer Rasmus Vissing ◽  
Niels Kjær Stampe ◽  
Kasper Rossing ◽  
Alex Hørby Christensen ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Screening ◽  
Sanger Sequencing ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Familial Dilated Cardiomyopathy ◽  
Pathogenic Variants ◽  
Case Summary ◽  
Heterozygous Carriers ◽  
Important Enzyme

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

scholarly journals Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Josef S. Herzog ◽  
Yanin Chavarri-Guerra ◽  
Danielle Castillo ◽  
Julio Abugattas ◽  
Cynthia Villarreal-Garza ◽  
...  
Keyword(s):  
Latin America ◽  
Latin American ◽  
Cancer Genomics ◽  
Low Cost ◽  
Probability Model ◽  
Copy Number Variant ◽  
Research Network ◽  
Community Research ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants

AbstractThe prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

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