scholarly journals Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions

2021 ◽  
Vol 12 ◽  
Author(s):  
Gergely Büki ◽  
Anna Zsigmond ◽  
Márta Czakó ◽  
Renáta Szalai ◽  
Gréta Antal ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Somatic Mosaicism ◽  
Clinical Manifestations ◽  
Comparative Genomic ◽  
Loss Of Function ◽  
Large Tumor ◽  
Large Deletions ◽  
Hands And Feet

Neurofibromatosis type 1 is a tumor predisposition syndrome inherited in autosomal dominant manner. Besides the intragenic loss-of-function mutations in NF1 gene, large deletions encompassing the NF1 gene and its flanking regions are responsible for the development of the variable clinical phenotype. These large deletions titled as NF1 microdeletions lead to a more severe clinical phenotype than those observed in patients with intragenic NF1 mutations. Around 5-10% of the cases harbor large deletion and four major types of NF1 microdeletions (type 1, 2, 3 and atypical) have been identified so far. They are distinguishable in term of their size and the location of the breakpoints, by the frequency of somatic mosaicism with normal cells not harboring the deletion and by the number of the affected genes within the deleted region. In our study genotype-phenotype analyses have been performed in 17 mostly pediatric patients with NF1 microdeletion syndrome identified by multiplex ligation-dependent probe amplification after systematic sequencing of the NF1 gene. Confirmation and classification of the NF1 large deletions were performed using array comparative genomic hybridization, where it was feasible. In our patient cohort 70% of the patients possess type-1 deletion, one patient harbors type-2 deletion and 23% of our cases have atypical NF1 deletion. All the atypical deletions identified in this study proved to be novel. One patient with atypical deletion displayed mosaicism. In our study NF1 microdeletion patients presented dysmorphic facial features, macrocephaly, large hands and feet, delayed cognitive development and/or learning difficulties, speech difficulties, overgrowth more often than patients with intragenic NF1 mutations. Moreover, neurobehavior problems, macrocephaly and overgrowth were less frequent in atypical cases compared to type-1 deletion. Proper diagnosis is challenging in certain patients since several clinical manifestations show age-dependency. Large tumor load exhibited more frequently in this type of disorder, therefore better understanding of genotype-phenotype correlations and progress of the disease is essential for individuals suffering from neurofibromatosis to improve the quality of their life. Our study presented additional clinical data related to NF1 microdeletion patients especially for pediatric cases and it contributes to the better understanding of this type of disorder.

Oral-Facial-Digital Syndrome Type 1: Further Clinical and Molecular Delineation in 2 New Families

2020 ◽  
Vol 57 (5) ◽  
pp. 606-615
Author(s):  
Sara Faily ◽  
Rahat Perveen ◽  
Kate Chandler ◽  
Jill Clayton-Smith
Keyword(s):  
Genetic Variants ◽  
Clinical Phenotype ◽  
Genetic Disorder ◽  
Molecular Diagnostic ◽  
Comparative Genomic ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Renal Anomalies ◽  
Whole Exome

Objective: Oral-facial-digital syndrome type 1 (OFD1) [OMIM 311200] is a rare genetic disorder associated with congenital anomalies of the oral cavity, face, and digits. This condition is associated with mutations in the OFD1 gene. Our objective was to recruit patients with the OFD1 clinical phenotype without genetic confirmation, aiming to identify genetic variants in the OFD1 gene. Design: Three patients from 2 unrelated families were recruited into our study. We employed a variety of genomic techniques on these patients, including candidate gene analysis, array comparative genomic hybridization, whole-exome sequencing, and whole-genome sequencing. Results: We investigated 3 affected patients from 2 unrelated families with a clinical diagnosis of OFD1. We discovered a novel pathogenic dominant missense mutation c.635G>C (p.Arg212Pro) in the OFD1 gene in one family. A novel frameshift, loss-of-function mutation c.306delA (p.Glu103LysfsTer42) was detected in the affected patient in the second family. Conclusions: These new genetic variants will add to the spectrum of known OFD1 mutations associated with the OFD1 disorder. Our study also confirms the variable phenotypic presentation of OFD1 and its well-recognized association with central nervous system malformations and renal anomalies. Molecular diagnostic confirmation achieved in these families will have positive implications for their medical management.

scholarly journals Neurofibromatosis: part 2 – clinical management

2015 ◽  
Vol 73 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Pollyanna Barros Batista ◽  
Eny Maria Goloni Bertollo ◽  
Danielle de Souza Costa ◽  
Lucas Eliam ◽  
Karin Soares Gonçalves Cunha ◽  
...  
Keyword(s):  
Clinical Management ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Cutaneous Manifestations ◽  
Wide Range ◽  
Reduced Rate ◽  
Present Text

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

Mutation Type As a Major Determinant of Clinical Phenotype in Myeloproliferative Neoplasms Associated with Mutant Calreticulin

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3215-3215 ◽  
Author(s):  
Daniela Pietra ◽  
Elisa Rumi ◽  
Chiara Milanesi ◽  
Christian A Di Buduo ◽  
Marta Bellini ◽  
...  
Keyword(s):  
Amino Acids ◽  
Clinical Phenotype ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Charged Amino Acids ◽  
Calr Mutations ◽  
Mutation Type ◽  
Calr Mutation

Abstract About 25% of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) carry a somatic mutation of CALR, the calreticulin gene [N Engl J Med. 2013;369:2379-90]. So far, more than 50 different indels in CALR exon 9 have been found, but a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2) are the most common lesions. All indels generate a novel C-terminus of the mutant protein, in which the endoplasmic reticulum retention signal KDEL is lost and the negatively charged amino acids are replaced by neutral and positively charged amino acids, disrupting the Ca-binding site. This suggests that both cellular dislocation and impaired Ca-binding activity may be involved in the abnormal proliferation of cells expressing a mutant calreticulin. It is still unclear, however, why the same mutant gene is associated with 2 different disease phenotypes (ET and PMF). In particular, little in known about the effect of the mutant protein on megakaryocyte biology and bone marrow collagen deposition. We studied the relationships between CALR mutation type, megakaryocyte biology, and clinical phenotype in patients with myeloproliferative neoplasms. According to the 2008 WHO criteria, 716 out of 892 patients had ET and 176 had PMF. Overall, 578 (65%) patients carried JAK2 (V617F), 230 (26%) had a CALR indel, and 84 (9%) had nonmutated JAK2 and CALR. Patients with MPL mutations were excluded. Twenty-six different types of CALR lesions were identified: 120 (52%) patients had type 1 mutation, 75 (33%) had type 2, and 35 (15%) carried other indels. The frequency of type 1 mutation was significantly higher in PMF than in ET (71% vs 46%, P=.004). All these variants involved 3 different stretches of negatively charged amino acids, with an increase in the isoelectric points (pI) of the mutant protein. As type 1 and type 2 mutations affected stretch I and III, respectively, the 26 indels were categorized into 3 groups on the basis of the stretch they affected: i) type 1-like (61%), affecting stretch I; ii) type 2-like (36%), stretch III; iii) and other types (3%), stretch II. The pI values were significantly different in the 3 groups (P<.001). The frequency of type-1 like mutations was significantly higher in PMF than in ET (82% vs 55%, P=.001). In vitro differentiated megakaryocytes from CALR-mutant patients displayed a significant increase in the extent of both intracellular Ca2+ release from the endoplasmic reticulum and extracellular Ca2+ entry inside the cytoplasm, as compared with healthy controls. Megakaryocytes carrying type 1-like CALR mutations exhibited the highest amplitude of Ca2+ flows regardless of the type of disease. In ET, impaired Ca2+ homeostasis was accompanied by atypical proplatelet architecture (ie, more branches and bifurcations). With respect to clinical phenotype at diagnosis, ET patients with type 2-like CALR mutation showed a trend towards higher PLT count (P=.063) and lower age (P=.053), and significantly lower LDH values (P=.021) than those with type 1-like mutation. In a hierarchical cluster analysis including demographic, clinical and molecular data, CALR mutation type (1 vs 2) identified the 2 clusters with the highest dissimilarity. Considering all patients, those with type 2-like CALR lesions had a better survival than those with JAK2 (V617F) (96.1% vs 84.4% at 10 years, P=.039), while no difference was found between the 2 CALR mutation types. ET patients with type 2-like CALR mutations showed a lower risk of thrombosis than those with JAK2 (V617F) (P=.010). By contrast, ET patients with type 1-like CALR mutations had a higher risk of myelofibrotic transformation that those with type 2-like CALR mutations (P=.029) and especially those with JAK2 (V617F) (P=.011). Finally, PMF patients with type 1-like CALR variants had a better survival than those with JAK2 (V617F) (80.1% vs 48% at 10 years, P=.008). In summary, abnormalities in megakaryocyte calcium metabolism and proplatelet architecture are found in patients with CALR-mutant myeloproliferative neoplasms, and their extent is related to mutation type. Type 2-like CALR mutations are more likely to be associated with isolated thrombocytosis without bone marrow fibrosis, ie, with an ET phenotype. By contrast, type 1-like CALR mutations are generally associated with bone marrow fibrosis, ie, with a PMF phenotype. Thus, in CALR-mutant myeloproliferative neoplasms, the mutation type is a major determinant of the clinical phenotype. Disclosures No relevant conflicts of interest to declare.

Domain Distribution of Type 1 VWD Sequence Variants and Impact on Clinical and Laboratory Phenotype in the Zimmerman Program

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 758-758
Author(s):  
Pamela A Christopherson ◽  
Veronica H Flood ◽  
Sandra L Haberichter ◽  
Daniel B Bellissimo ◽  
Kenneth D Friedman ◽  
...  
Keyword(s):  
Splice Site ◽  
Clinical Severity ◽  
Comparative Genomic ◽  
Sequence Variant ◽  
Sequence Variants ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Large Deletions ◽  
Von Willebrand

Type 1 von Willebrand disease (VWD) is a common inherited bleeding disorder, characterized by a quantitative deficiency of von Willebrand factor (VWF). The molecular basis continues to merit exploration, especially since the genetic cause has not been determined in 30-40% of cases in previous studies. As part of the Zimmerman Program for the Molecular and Biology of VWD (ZPMCB-VWD) study, we sought to identify the sequence variants (SV) within the VWF gene that result in type 1 VWD and correlate these to clinical laboratory phenotype and clinical severity and determine the frequency of type 1 subjects who do not have a gene defect. We also wanted to examine the types of sequence variants that cause type 1, type 1-Severe (1S), type 1C and low VWF (LVWF), and determine the influence of SV location on VWF levels and risk of bleeding. 310 type 1 Index Cases (IC) enrolled in the ZPMCB-VWD were analyzed, including 69 type 1 (VWF:Ag<30), 9 type 1S (VWF:Ag<5), 57 type 1C (VWF:Ag<30; VWFpp/VWF:Ag>3), and 175 LVWF (VWF:Ag or VWF:RCo 30-50). Bleeding symptoms were quantified using the ISTH bleeding score (ISTH BS). Clinical VWF testing was done in a central laboratory at BloodCenter of Wisconsin and included FVIII, VWF:Ag, VWF:RCo, VWFpp, and VWF:CB. Full-length VWF sequencing was performed, including 5' and 3' regions and intron/exon boundaries. SV found in >1% of the healthy control population were excluded from this analysis. Mutation negative cases were further investigated by comparative genomic hybridization (CGH) to identify any large deletions or duplications in the VWF gene. SV or large deletions were identified in 62% (n=192) of this cohort with quantitative VWF deficiency, whereas 38% (n=118) had no variants found. Of those with no sequence variant identified, 10% were type 1, 5% type 1C and 85% LVWF. There were 142 SV found in this cohort. 75% of the subjects had missense mutations, 8% small insertions/deletions, 9% splice site mutations, 3% nonsense mutations and 1% large deletions. The median number of SV found in individuals was 1, however 23% had more than 1 SV present (range 1 to 4). Mean VWF:Ag (IU/dl) was examined to determine the influence of SV location on levels and median ISTH BS was assessed as a measure of bleeding severity by domain: Table.VWF DomainD1D2D'D3A1A2A3D4C1-C6CKNone# Subjects24343460251324304118VWF:Ag (IU/dl)18211614311221253839ISTH BS5665495515 Type 1S subjects had SV that were enriched in D1, D2 and A3 domains. 52% of type 1C variants were found in the A1 domain followed by 19% in D'D3 and 17% in D4. Both type 1 and LVWF subjects had SV that were evenly distributed throughout the gene, but LVWF had the majority of SV found in the A2, D2 and C1-C6 domains. Type 1S subjects showed a difference in mutation type compared to rest of the type 1 cohort with 31% intronic/splice site mutations, 19% nonsense mutations, 19% insertions/deletions and only 25% missense mutations. In contrast, missense mutations accounted for 68% of the mutations in type 1, 91% in type 1C and 80% in LVWF. The presence of predominantly truncating or loss of function variants in type 1S correlates with lower VWF levels and increased bleeding. In conclusion, we found that 62% of our type 1 cohort did have potentially causative SVs identified, with the majority caused by missense mutations (75%). Type 1C and type 1S tend to have SV isolated in certain domains whereas SV in type 1 and LVWF tend to be spread throughout the gene. SVs in the A3 domain demonstrated the lowest VWF:Ag (12 IU/dl) and highest ISTH BS (9) while changes in the CK domain had the highest VWF:Ag (38 IU/dl) and lowest ISTH BS (1). SVs or large deletions were not found in 38% of this cohort, indicating that other molecular factors either intronic or outside of the VWF gene may be the cause of low VWF and bleeding in these subjects. Disclosures Friedman: CSL Behring: Consultancy; Instrumentation Laboratories: Consultancy; Novo Nordisk: Consultancy; Alexion: Speakers Bureau. Gill:Baxalta, Bayer, and CSL-Behring: Membership on an entity's Board of Directors or advisory committees.

Gene expression profiling identifies two distinct papillary renal cell carcinoma (RCC) subgroups of contrasting prognosis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4503-4503
Author(s):  
B. T. Teh ◽  
X. J. Yang ◽  
M. Tan ◽  
H. L. Kim ◽  
W. Stadler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Papillary Renal Cell Carcinoma ◽  
Comparative Genomic ◽  
Low Grade ◽  
Class 1

4503 Background: Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphological classification of PRCC into Type 1 and Type 2 tumors has been recently proposed, but its biological relevance remains uncertain. Methods: We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analysis. Comparative genomic microarray analysis (CGMA) was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples, with 15 independent tumors. Results: We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histological subtypes: Type 1, low-grade Type 2 and mixed Type 1/low-grade Type 2 tumors. The second class, with poor survival, corresponded to high-grade Type 2 tumors (n = 11). Dysregulation of G1/S and G2/M checkpoint genes were found in Class 1 and Class 2 tumors respectively, alongside characteristic chromosomal aberrations. We identified a 7-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in Class 1 tumors, and of topoisomerase IIα in Class 2 tumors. Conclusions: We report two molecular subclasses of PRCC, which are biologically and clinically distinct, which may be readily distinguished in a clinical setting. This may also have therapeutic implications. No significant financial relationships to disclose.

scholarly journals Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis

2016 ◽  
Vol 57 (3) ◽  
pp. R127-R142 ◽  
Author(s):  
Fadil M Hannan ◽  
Valerie N Babinsky ◽  
Rajesh V Thakker
Keyword(s):  
G Protein ◽  
Hormone Secretion ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Loss Of Function ◽  
Mineral Density ◽  
Gain Of Function ◽  
Type 3

The extracellular calcium (Ca2+o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca2+o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca2+o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH). However, CASR mutations are only detected in ≤70% of FHH and ADH cases, referred to as FHH type 1 and ADH type 1, respectively, and studies in other FHH and ADH kindreds have revealed these disorders to be genetically heterogeneous. Thus, loss- and gain-of-function mutations of the GNA11 gene on chromosome 19p13.3, which encodes the G-protein α-11 (Gα11) subunit, lead to FHH type 2 and ADH type 2, respectively; whilst loss-of-function mutations of AP2S1 on chromosome 19q13.3, which encodes the adaptor-related protein complex 2 sigma (AP2σ) subunit, cause FHH type 3. These studies have demonstrated Gα11 to be a key mediator of downstream CaSR signal transduction, and also revealed a role for AP2σ, which is involved in clathrin-mediated endocytosis, in CaSR signalling and trafficking. Moreover, FHH type 3 has been demonstrated to represent a more severe FHH variant that may lead to symptomatic hypercalcaemia, low bone mineral density and cognitive dysfunction. In addition, calcimimetic and calcilytic drugs, which are positive and negative CaSR allosteric modulators, respectively, have been shown to be of potential benefit for these FHH and ADH disorders.

scholarly journals Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
N. B. Toppings ◽  
J. M. McMillan ◽  
P. Y. B. Au ◽  
O. Suchowersky ◽  
L. E. Donovan
Keyword(s):  
Diabetes Mellitus ◽  
Optic Atrophy ◽  
Cell Function ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Wolfram Syndrome ◽  
Biallelic Mutations ◽  
Therapeutic Considerations

Background.Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations inWFS1,a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care.Case.We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations inWFS1were identified, supporting a diagnosis of classical WS.Conclusions.The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserveβ-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies forβ-cell preservation for individuals with type 1 and 2 diabetes.

scholarly journals Nocturnal Hypoglycemia in Type 2 Diabetes

2018 ◽  
Vol 25 (1) ◽  
pp. 99-103
Author(s):  
Simona Clus ◽  
Gabriela Crețeanu ◽  
Amorin Popa
Keyword(s):  
Type 2 Diabetes ◽  
Disease Duration ◽  
Clinical Manifestations ◽  
Glucose Monitoring ◽  
Glucose Variability ◽  
Ambulatory Setting ◽  
Pharmacological Interventions ◽  
Nocturnal Hypoglycemia

Abstract Background and aims: It is known that the majority of critical unacknowledged hypoglycemia has an increased incidence in patients with type 1 diabetes (T1DM) with a long evolution. The aim of this research is to evaluate the variability of glucose level and hypoglycemic events in patients with type 2 diabetes (T2DM) having pharmacological interventions with hypoglycemic risk. These events are sometimes asymptomatic also in T2DM: frequently in elderly, patients with autonomic neuropathy, or having a long evolution of disease. Material and method: This analysis includes 72 patients with T2DM, with a relative good metabolic control, and possible glucose fluctuations. Glucose variability was appreciated using continuous glucose monitoring systems (CGMS) used for more than 72 hours in hospital or ambulatory setting. Results: The incidence, duration and severity of hypoglycemia are not correlated with HbA1c value, age, disease duration or treatment. Approximately a quarter of patients had nocturnal hypoglycemia and in 37,5% of events hypoglycemia was prolonged, more 45 minutes. Clinical manifestations in diurnal hypoglycemia were presents in only 40% of the recorded events. Conclusions: The study suggested that CGMS is beneficial for patients with type 2 diabetes, with hypoglycemic risk and complications, to adjusted medication, education and prevention the cardiovascular events.

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