scholarly journals Description of a SDHD c.129G>A (p.W43X) Mutation With Variable Presentation in Multiple Family Members

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A995-A995
Author(s):  
Samantha Greenberg ◽  
Buchmann Luke ◽  
Anne Naumer ◽  
Wendy Kohlmann ◽  
Kinley Garfield ◽  
...  
Keyword(s):  
Family Members ◽  
Tumor Development ◽  
Large Family ◽  
Recurrence Rates ◽  
Pathogenic Variants ◽  
Bilateral Carotid ◽  
Age Of Diagnosis ◽  
Inherited Mutations ◽  
Variable Penetrance ◽  
First Diagnosis

Abstract Approximately 40% of paragangliomas and pheochromocytomas are attributed to hereditary mutations. SDHD mutations account for 7% of inherited mutations (PGL1 syndrome), is maternally imprinted and has variable penetrance. SDHD pathogenic variants (PV) have been previously described extensively in Dutch pedigrees, with a varying lifetime risk for tumor development. Here we report a large family (Fig 1) displaying a SDHD c.129G>A (p.W43X) variation in 12 family members, 10 of whom had screening or tumor history available. The presentation and age of diagnosis in family members showed variable penetrance. Age at first diagnosis of a pheochromocytoma/paraganglioma ranged from 10 - 45 years. Family members displayed bilateral pheochromocytomas, bilateral carotid body tumors, and paragangliomas of the head, neck and trunk with variable recurrence rates (none to multiple). No malignant lesions were detected to date. Pheochromocytomas were norepinephrine producing. Paragangliomas ranged from non-functional to dopamine and norepinephrine producing. Compared to previous reports of other SDHD mutations, the SDHD c.129G>A (p.W43X) variation displayed an earlier age at first diagnosis with a highly variable phenotype ranging from one benign, non-secreting paraganglioma to bilateral pheochromocytomas and recurrent parganagliomas along the parasympathetic chain from head to abdomen. This report contributes to the evolving understanding of the phenotypic presentations of various genetic mutations. We propose that expert guidelines that suggest screening family members with the SDHD c.129G>A (p.W43X) variation at the age of 8 for early detection of pheochromocytomas and paragangliomas is beneficial.

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 Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Elisabeth A. Rosenthal ◽  
David R. Crosslin ◽  
Adam S. Gordon ◽  
David S. Carrell ◽  
Ian B. Stanaway ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Large Family ◽  
Missense Variant ◽  
Mixed Ancestry ◽  
Limited Sample ◽  
Health Records ◽  
Pathogenic Variants ◽  
Phenotype Data ◽  
Emerge Network ◽  
Using Data

Abstract Background Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. Methods Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. Results We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. Conclusions Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.

scholarly journals Assessment of genetic referrals and outcomes for women with triple negative breast cancer in regional cancer centres in Australia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lucie G. Hallenstein ◽  
Carol Sorensen ◽  
Lorraine Hodgson ◽  
Shelly Wen ◽  
Justin Westhuyzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Genetics ◽  
Eligibility Criteria ◽  
Pathogenic Variants ◽  
Genetics Services ◽  
Age Of Diagnosis ◽  
Over Time

Abstract Background Guidelines for referral to cancer genetics service for women diagnosed with triple negative breast cancer have changed over time. This study was conducted to assess the changing referral patterns and outcomes for women diagnosed with triple negative breast cancer across three regional cancer centres during the years 2014–2018. Methods Following ethical approval, a retrospective electronic medical record review was performed to identify those women diagnosed with triple negative breast cancer, and whether they were referred to a genetics service and if so, the outcome of that genetics assessment and/or genetic testing. Results There were 2441 women with newly diagnosed breast cancer seen at our cancer services during the years 2014–2018, of whom 237 women were diagnosed with triple negative breast cancer. Based on age of diagnosis criteria alone, 13% (31/237) of our cohort fulfilled criteria for genetic testing, with 81% (25/31) being referred to a cancer genetics service. Of this group 68% (21/31) were referred to genetics services within our regions and went on to have genetic testing with 10 pathogenic variants identified; 5x BRCA1, 4x BRCA2 and × 1 ATM:c.7271 T > G. Conclusions Referral pathways for women diagnosed with TNBC to cancer genetics services are performing well across our cancer centres. We identified a group of women who did not meet eligibility criteria for referral at their time of diagnosis, but would now be eligible, as guidelines have changed. The use of cross-discipline retrospective data reviews is a useful tool to identify patients who could benefit from being re-contacted over time for an updated cancer genetics assessment.

scholarly journals Contribution of Genetic and Environmental Risk Factors in a Juvenile Idiopathic Arthritis Large Family With SERPINA1 Gene Mutations

2021 ◽  
Author(s):  
Cyprian Popescu
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Gene Mutations ◽  
Large Family ◽  
Carrier Status ◽  
Multiplex Family ◽  
Serpina1 Gene ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genetic And Environmental Factors ◽  
Underlying Mechanisms

Abstract Objectives Although the underlying mechanisms and mediators of arthritis in juvenile idiopathic arthritis (JIA) are not well understood, accumulated evidence supports the mixt role of genetic and environmental factors. Few reports of multiplex families with JIA were published until now. The aim of this study was to identify new genetic or environmental associations concerning the patients of a kindred with juvenile idiopathic arthritis and psoriatic features (JIAPs). Methods Here, we characterized an extended multiplex family of 5 patients with juvenile idiopathic arthritis and psoriatic features (PsA) at the clinical and genetic level, using whole exome sequencing. Results We did not confirm in our family the linkage with the genetic factors already described that might be associated with increase susceptibility to JIA. We found a carrier status of siblings who inherited a pathogenic allele of the SERPINA1 gene from their mother who herself has two heterozygous pathogenic variants in the SERPINA1 gene. Conclusions Our data showed that JIA results from pleiotropic effects of environmental background with an only minor monogenic contribution. Even that a monogenetic factor could not be proved, some genetic factor as SERPINA1 mutations which can sensitize for psoriatic arthritis development seems to be involved. Further investigation must be done to prove whether SERPINA1 mutations may have a potential JIA causality.

Innexin-3 forms connexin-like intercellular channels

1999 ◽  
Vol 112 (14) ◽  
pp. 2391-2396 ◽  
Author(s):  
Y. Landesman ◽  
T.W. White ◽  
T.A. Starich ◽  
J.E. Shaw ◽  
D.A. Goodenough ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Gap Junction ◽  
Functional Properties ◽  
Xenopus Oocytes ◽  
Family Members ◽  
Electrical Coupling ◽  
Large Family ◽  
Gap Junction Channel ◽  
Intercellular Channels

Innexins comprise a large family of genes that are believed to encode invertebrate gap junction channel-forming proteins. However, only two Drosophila innexins have been directly tested for the ability to form intercellular channels and only one of those was active. Here we tested the ability of Caenorhabditis elegans family members INX-3 and EAT-5 to form intercellular channels between paired Xenopus oocytes. We show that expression of INX-3 but not EAT-5, induces electrical coupling between the oocyte pairs. In addition, analysis of INX-3 voltage and pH gating reveals a striking degree of conservation in the functional properties of connexin and innnexin channels. These data strongly support the idea that innexin genes encode intercellular channels.

scholarly journals Hepatic Thermal Injury Promotes Colorectal Cancer Engraftment in C57/black 6 Mice

2020 ◽  
Author(s):  
Alison L. Halpern ◽  
J. Gregory Fitz ◽  
Yuki Fujiwara ◽  
Jeniann Yi ◽  
Aimee L. Anderson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thermal Ablation ◽  
Thermal Injury ◽  
Tumor Development ◽  
Hepatic Metastases ◽  
Local Environment ◽  
Surgical Approaches ◽  
Recurrence Rates ◽  
Poor Outcomes ◽  
Argon Beam Coagulation

Background:Treatment of liver metastases (primarily colorectal cancer) is limited by high recurrence rates and tumor progression. Surgical approaches to management of these metastases typically utilize heat energy: including electrocautery; argon beam coagulation; thermal ablation of surgical margins for hemostasis; and preemptive thermal ablation to prevent bleeding or effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of pro-cancer cytokines and deleterious immune infiltrates at the site of thermal injury. Approach and Results:To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Further, there were local increases in expression of mRNA for Hif1a, Arg1, and Vegfaand activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (p=0.03). Conclusions:Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with pro-tumorigenic activation of macrophages and circulating tumors implanting. Discrete targeting of HIF1α and/or its up and downstream pathways and/or inhibiting macrophages offer potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is utilized.

scholarly journals Novel p.G1344E mutation in FBN1 is associated with ectopia lentis

2020 ◽  
pp. bjophthalmol-2019-315265
Author(s):  
Yuan Yang ◽  
Ya-li Zhou ◽  
Teng-teng Yao ◽  
Hui Pan ◽  
Ping Gu ◽  
...  
Keyword(s):  
Late Onset ◽  
Family Members ◽  
Crystalline Lens ◽  
Pathogenic Mutation ◽  
Ectopia Lentis ◽  
Skeletal Involvement ◽  
Suspensory Ligament ◽  
Pathogenic Variants ◽  
Fibrillin 1 ◽  
Systemic Examination

BackgroundEctopia lentis refers to dislocation or subluxation of the crystalline lens. Fibrillin-1, encoded by FBN1, is an important microfibrillar structural component that is specifically required for the suspensory ligament of the lens. FBN1 mutations may cause abnormal structure of microfibrils and has been associated with a broad spectrum of clinical phenotypes. In this study, we characterised a Chinese dominant family with late-onset isolated ectopia lentis caused by a novel missense FBN1 mutation.MethodsEight family members, including four patients with suspected isolated ectopia lentis, were recruited from Shanghai. Clinical data and family history of the proband and other affected family members were collected. Ophthalmic examination, systemic examination and echocardiography were performed. Whole exome sequencing and Sanger sequencing were used to detect potential pathogenic variants.ResultsA novel heterozygous missense mutation c.4031 G>A/p.Gly1344Glu in exon 33 of FBN1 was identified. This mutation was detected in all affected family members and led to specific ocular system phenotypes (ectopia lentis, microspherophakia and secondary glaucoma) with minor skeletal involvement (hallux valgus).ConclusionThe novel c.4031G>A mutation in FBN1 is a likely pathogenic mutation for isolated ectopia lentis. Our study expands the spectrum of FBN1 mutations and contributes to better comprehension of genotype-phenotype correlations of ectopia lentis disease.

scholarly journals Expression, purification, crystallization and preliminary crystallographic analysis of human myotubularin-related protein 3

2014 ◽  
Vol 70 (9) ◽  
pp. 1240-1243
Author(s):  
Ji Young Son ◽  
Jee Un Lee ◽  
Ki-Young Yoo ◽  
Woori Shin ◽  
Dong-Won Im ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Catalytic Domain ◽  
Family Members ◽  
Large Family ◽  
Crystallographic Analysis ◽  
Related Protein ◽  
Unit Cell Parameters ◽  
X Ray ◽  
Cell Parameters ◽  
Related Proteins

Myotubularin-related proteins are a large family of phosphatases that have the catalytic activity of dephosphorylating the phospholipid molecules phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Each of the 14 family members contains a phosphatase catalytic domain, which is inactive in six family members owing to amino-acid changes in a key motif for the activity. All of the members also bear PH-GRAM domains, which have low homologies between them and have roles that are not yet clear. Here, the cloning, expression, purification and crystallization of human myotubularin-related protein 3 encompassing the PH-GRAM and the phosphatase catalytic domain are reported. Preliminary X-ray crystallographic analysis shows that the crystals diffracted to 3.30 Å resolution at a synchrotron X-ray source. The crystals belonged to space groupC2, with unit-cell parametersa= 323.3,b= 263.3,c= 149.4 Å, β = 109.7°.

Familial multicentric paragangliomas in a child

1991 ◽  
Vol 105 (5) ◽  
pp. 376-380 ◽  
Author(s):  
Dov Ophir
Keyword(s):  
Carotid Body ◽  
Family Members ◽  
Surgical Removal ◽  
Inheritance Pattern ◽  
Cerebellar Astrocytoma ◽  
Rare Combination ◽  
Bilateral Carotid ◽  
Operative Evaluation ◽  
Mediastinal Paraganglioma

AbstractA 12-year-old girl presented with bilateral carotid-body paragangliomas and a unilateral jugular paraganglioma. The tumours were surgically removed. This is a rare combination of tumours in any patient and previously unreported in a child of this age. Her father died of a cerebellar astrocytoma and her mother underwent surgical removal of a large mediastinal paraganglioma. The association of astrocytoma with familial paragangliomas has never been documented. The literature on the epidemiology and inheritance pattern of familial paragangliomas is reviewed. The need for thorough pre-operative evaluation of the patient and close follow-up of family members is stressed.

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.

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