Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

2018 ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Aortic Disease ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

scholarly journals Monogenic causes in the Type 1 Diabetes Genetics Consortium cohort; low genetic risk for autoimmunity in case selection

2021 ◽  
Author(s):  
Luc Marchand ◽  
Meihang Li ◽  
Coralie Leblicq ◽  
Ibrar Rafique ◽  
Tugba Alarcon-Martinez ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Large Scale ◽  
Wolfram Syndrome ◽  
Monogenic Diabetes ◽  
Therapeutic Implications ◽  
Pathogenic Variants ◽  
Affected Parent ◽  
Diabetes Genetics

Abstract: Hypothesis About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection. Methods As proof of principle, we examined by exome sequencing families with two or more children, recruited by the Type 1 Diabetes Genetics Consortium and selected for negativity for two autoantibodies and absence of risk HLA haplotypes. Results We examined 46 families that met the criteria. Of the 17 with an affected parent, seven (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including five with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones. Conclusions Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that non-syndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.

scholarly journals Germinal defects of SDHx genes in patients with isolated pituitary adenoma

2020 ◽  
Vol 183 (4) ◽  
pp. 369-379
Author(s):  
Grégory Mougel ◽  
Arnaud Lagarde ◽  
Frédérique Albarel ◽  
Wassim Essamet ◽  
Perrine Luigi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Pituitary Adenoma ◽  
Family History ◽  
Age Of Onset ◽  
Personal History ◽  
Pathogenic Variants ◽  
Predisposing Genes ◽  
History Of ◽  
New Gateway

Background: The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

scholarly journals Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age

2020 ◽  
Vol 8 (1) ◽  
pp. e001345
Author(s):  
Yunting Lin ◽  
Huiying Sheng ◽  
Tzer Hwu Ting ◽  
Aijing Xu ◽  
Xi Yin ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Genetic Testing ◽  
Age Of Onset ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Chinese Patients ◽  
Combination Strategy ◽  
Southern Chinese ◽  
Whole Exome ◽  
Design And Methods

IntroductionA specific molecular diagnosis of monogenic diabetes mellitus (MDM) will help to predict the clinical course and guide management. This study aims to identify the causative genes implicated in Chinese patients with MDM with onset before 3 years of age.Research design and methods71 children with diabetes mellitus (43 diagnosed before 6 months of age, and 28 diagnosed between 6 months and 3 years of age who were negative for diabetes-associated autoantibodies) underwent genetic testing with a combination strategy of Sanger sequencing, chromosome microarray analysis and whole exome sequencing. They were categorized into four groups according to the age of onset of diabetes (at or less than 6 months, 6 to 12 months, 1 to 2 years, 2 to 3 years) to investigate the correlation between genotype and phenotype.ResultsGenetic abnormalities were identified in 39 of 71 patients (54.93%), namely KCNJ11 (22), ABCC8 (3), GCK (3), INS (3), BSCL2 (1) and chromosome abnormalities (7). The majority (81.40%, 35/43) of neonatal diabetes diagnosed less than 6 months of age and 33.33% (3/9) of infantile cases diagnosed between 6 and 12 months of age had a genetic cause identified. Only 11.11% (1/9) of cases diagnosed between 2 and 3 years of age were found to have a genetic cause, and none of the 10 patients diagnosed between 1 and 2 years had a positive result in the genetic analysis. Vast majority or 90.48% (19/21) of patients with KCNJ11 (19) or ABCC8 (2) variants had successful switch trial from insulin to oral sulfonylurea.ConclusionsThis study suggests that genetic testing should be given priority in diabetes cases diagnosed before 6 months of age, as well as those diagnosed between 6 and 12 months of age who were negative for diabetes-associated autoantibodies. This study also indicates significant impact on therapy with genetic cause confirmation.

scholarly journals Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

2019 ◽  
Vol 12 (6) ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby ◽  
Dongchuan Guo ◽  
Wei Zhou ◽  
Maoxuan Lin ◽  
...  
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Age Of Onset ◽  
Family Members ◽  
Aortic Disease ◽  
Pathogenic Variant ◽  
Carrier Status ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

scholarly journals Strategies to identify individuals with monogenic diabetes: results of an economic evaluation

BMJ Open ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. e034716 ◽  
Author(s):  
Jaime L Peters ◽  
Rob Anderson ◽  
Beverley Shields ◽  
Sophie King ◽  
Michelle Hudson ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Characteristics ◽  
Treatment Strategies ◽  
Monogenic Diabetes ◽  
Blood Glucose Monitoring ◽  
Current Evidence ◽  
Secondary Outcome ◽  
Diabetes Diagnosis ◽  
Lifetime Costs ◽  
Test Treatment

ObjectivesTo evaluate and compare the lifetime costs associated with strategies to identify individuals with monogenic diabetes and change their treatment to more appropriate therapy.DesignA decision analytical model from the perspective of the National Health Service (NHS) in England and Wales was developed and analysed. The model was informed by the literature, routinely collected data and a clinical study conducted in parallel with the modelling.SettingSecondary care in the UK.ParticipantsSimulations based on characteristics of patients diagnosed with diabetes <30 years old.InterventionsFour test-treatment strategies to identify individuals with monogenic diabetes in a prevalent cohort of diabetics diagnosed under the age of 30 years were modelled: clinician-based genetic test referral, targeted genetic testing based on clinical prediction models, targeted genetic testing based on biomarkers, and blanket genetic testing. The results of the test-treatment strategies were compared with a strategy of no genetic testing.Primary and secondary outcome measuresDiscounted lifetime costs, proportion of cases of monogenic diabetes identified.ResultsBased on current evidence, strategies using clinical characteristics or biomarkers were estimated to save approximately £100–£200 per person with diabetes over a lifetime compared with no testing. Sensitivity analyses indicated that the prevalence of monogenic diabetes, the uptake of testing, and the frequency of home blood glucose monitoring had the largest impact on the results (ranging from savings of £400–£50 per person), but did not change the overall findings. The model is limited by many model inputs being based on very few individuals, and some long-term data informed by clinical opinion.ConclusionsCosts to the NHS could be saved with targeted genetic testing based on clinical characteristics or biomarkers. More research should focus on the economic case for the use of such strategies closer to the time of diabetes diagnosis.Trial registration numberNCT01238380.

Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Exome Sequencing

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 267-OR
Author(s):  
SEUNG SHIN PARK ◽  
SE SONG JANG ◽  
YOUNG AH LEE ◽  
YOUNG MIN CHO ◽  
HAK CHUL JANG ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Monogenic Diabetes ◽  
Targeted Exome Sequencing ◽  
Pathogenic Variants

Autosomal recessive hereditary spastic paraplegia: a rare case of a family with phenotypic variation

2020 ◽  
Vol 17 ◽  
Author(s):  
Mor Saban ◽  
Tal Shachar
Keyword(s):  
Genetic Testing ◽  
Phenotypic Variation ◽  
Hereditary Spastic Paraplegia ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Treatment Options ◽  
Family Members ◽  
Complex Form ◽  
Single Family ◽  
Spastic Paraplegia

Background: Hereditary spastic paraplegia is a neurodegenerative disorder with a pure and complex form. More than 50 genetic types are currently known, with different ages of onset for characteristic symptoms. Data regarding hereditary spastic paraplegia remain scarce, and the rare subtype of spastic paraplegia type 5 is no exception. Objective: This report presents data regarding the case of a single family, from the city of Djerba, with five individuals affected with hereditary spastic paraplegia, the largest number of spastic paraplegia type 5 mutated family members so far reported in current literature. Methods: To emphasize the importance of genetic testing, we retrospectively reviewed a familial confirmed case of hereditary spastic paraplegia. Clinical features of family members were described. Results: The family presents a large phenotypic variation that in part differs from the known phenotypic presentations. Age of onset and clinical manifestation showed interfamilial variations. The alteration found in CYP7B1 (c.1081C>T; p.R361*) may help emphasize the importance of genetic testing and the much-needed treatment options already in use in current neurological practice. Conclusion: The understanding of the molecular pathways of hereditary spastic paraplegia, together with the establishment of disease biomarkers, will hopefully lead to better, and more personalized treatment.

scholarly journals Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2368
Author(s):  
Heidi G. Sutherland ◽  
Neven Maksemous ◽  
Cassie L. Albury ◽  
Omar Ibrahim ◽  
Robert A. Smith ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Factors ◽  
Sequencing Data ◽  
Hemiplegic Migraine ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.

scholarly journals Mutation Frequency in Main Susceptibility Genes Among Patients With Head and Neck Paragangliomas

2020 ◽  
Vol 11 ◽  
Author(s):  
Anastasiya V. Snezhkina ◽  
Maria S. Fedorova ◽  
Vladislav S. Pavlov ◽  
Dmitry V. Kalinin ◽  
Alexander L. Golovyuk ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Head And Neck ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mutation Frequency ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
High Degree ◽  
Head And Neck Paragangliomas

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors that have a high degree of heritability and are predominantly associated with mutations in ten genes, such as SDHx, SDHAF2, VHL, RET, NF1, TMEM127, MAX, FH, MEN2, and SLC25A11. Elucidating the mutation prevalence is crucial for the development of genetic testing. In this study, we identified pathogenic/likely pathogenic variants in the main susceptibility genes in 102 Russian patients with HNPGLs (82 carotid and 23 vagal paragangliomas) using whole exome sequencing. Pathogenic/likely pathogenic variants were detected in 43% (44/102) of patients. We identified the following variant distribution of the tested genes: SDHA (1%), SDHB (10%), SDHC (5%), SDHD (24.5%), and RET (5%). SDHD variants were observed in the majority of the patients with bilateral/multiple paragangliomas. Thus, among Russian patients with HNPGLs the most frequently mutated gene was SDHD followed by SDHB, SDHC, RET, and SDHA.

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