Ellen S. Regalado

Invitae (United States)

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Dianna M. Milewicz

The University of Texas Health Science Center at Houston

Dongchuan Guo

The University of Texas Health Science Center at Houston

Deborah A. Nickerson

University of Washington

Suzanne M. Leal

Columbia University Irving Medical Center

Guillaume Jondeau

Hôpital Bichat-Claude-Bernard

Michael J. Bamshad

University of Washington

Cathérine Boileau

Assistance Publique – Hôpitaux de Paris

Anthony L. Estrera

The University of Texas Health Science Center at Houston

Scott A. LeMaire

Baylor College of Medicine

Ellen M. Hostetler

The University of Texas Health Science Center at Houston

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National Institute on Population Medical Genetics

165

The University of Texas Health Science Center at Houston

Baylor College of Medicine

Inserm

University of Washington

Harvard University

University of Michigan–Ann Arbor

Assistance Publique – Hôpitaux de Paris

Massachusetts General Hospital

Stanford University

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Molecular Genetics of Aortic Aneurysms and Aortic Dissections

Encyclopedia of Life Sciences (2015)

Ellen S. Regalado Dianna M. Milewicz

Abstract A genetic predisposition to aortic aneurysms and dissections can occur as part of a genetic syndrome, such as Marfan and Loeys‐Dietz syndrome, or as an isolated manifestation without other systemic features, referred to as familial thoracic aortic aneurysms and dissections. These genetic disorders are inherited as autosomal dominant conditions with reduced penetrance and variable expressivity in terms of aortic disease presentation, age of onset and extent of cardiovascular and other systemic involvement. Mutations in the FBN1 , TGFBR1 , TGFBR2 , SMAD3 , SMAD4 , TGFB2 , ACTA2 , MYH11 , MYLK and PRKG1 have been identified in patients with syndromic and non‐syndromic TAAD, emphasising the important roles of the transcription growth factor beta signalling pathway and smooth muscle contraction in aortic disease development. Key Concepts Thoracic aortic aneurysms and dissections or TAAD can occur as part of a genetic syndrome, such as Marfan syndrome, Loeys‐Dietz syndrome or as an isolated manifestation without syndromic features. Approximately 20% of patients with TAAD who do not have Marfan syndrome or related disorder have a similarly affected relative, referred to as familial thoracic aortic aneurysm and dissection or FTAAD. Marfan syndrome, Loeys‐Dietz syndrome and FTAAD are primarily inherited in an autosomal dominant pattern with reduced penetrance and variable expressivity. FTAAD is a genetically and clinically heterogeneous group of disorders caused by mutations in several genes, including FBN1 , TGFBR1 , TGFBR2 , SMAD3 , SMAD4 , TGFB2 , ACTA2 , MYH11 , MYLK and PRKG1 .

Penetrance

Thoracic aortic aneurysm

Expressivity

Genetic disorder

10.1002/9780470015902.a0024366

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Citations (2)

MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms

The American Journal of Human Genetics (2014)

Dongchuan Guo Limin Gong Ellen S. Regalado Regie Lyn P. Santos‐Cortez Zhao Ren

Thoracic aortic aneurysm

10.1016/j.ajhg.2014.11.015

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Citations (100)

Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms

American Journal of Medical Genetics Part A (2011)

Ellen S. Regalado Sarah Medrek Van Tran‐Fadulu Dongchuan Guo Hariyadarshi Pannu

Abstract A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation ( P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty‐nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1 , TGFBR2 , and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections. © 2011 Wiley‐Liss, Inc.

Penetrance

Thoracic aortic aneurysm

Genetic predisposition

10.1002/ajmg.a.34050

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Citations (47)

Use of genetics for personalized management of heritable thoracic aortic disease: How do we get there?

Journal of Thoracic and Cardiovascular Surgery (2014)

Dianna M. Milewicz Ellen S. Regalado

Thoracic aortic aneurysm

Thoracic aorta

Acute aortic syndrome

10.1016/j.jtcvs.2014.07.070

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Citations (51)

Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections

PLoS ONE (2016)

Siddharth K. Prakash Shao-Qing Kuang Ellen S. Regalado Dongchuan Guo Dianna M. Milewicz

Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

Proband

Thoracic aortic aneurysm

10.1371/journal.pone.0153543

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Citations (38)

Phenotypic and genetic diversity of rice seed-associated bacteria and their role in pathogenicity and biological control

Journal of Applied Microbiology (2009)

B. G. Cottyn Jane Debode Ellen S. Regalado T. W. Mew Jean Swings

To study the phenotypic and genetic diversity of culturable bacteria associated with rice seed and to asses the antagonistic and pathogenic potential of the isolated bacteria.Seed of rice cultivar PSBRc14 was collected from farmers' fields of irrigated lowland in southern Luzon, Philippines. Isolations of distinct colonies yielded 498 isolates. Classification of the isolates according to similarities in cellular characteristics, whole-cell fatty acid composition, and colony appearance differentiated 101 morphotype groups. Predominant bacteria were Coryneform spp., Pantoea spp. and Pseudomonas spp. Other bacteria regularly present were Actinomycetes spp., Bacillus pumilus, B. subtilis, Burkholderia glumae, Enterobacter cloacae, Paenibacillus polymyxa, Staphylococcus spp. and Xanthomonas spp. The genetic diversity among isolates was assessed by BOX-PCR fingerprinting of genomic DNA and represented 284 fingerprint types (FPTs). Most FPTs (78%) were not shared among samples, while eight FPTs occurred frequently in the samples. Seven of these FPTs also occurred frequently in a previous collection made from rainfed lowlands of Iloilo island, Philippines. Sixteen per cent of the isolates inhibited in vitro the mycelial growth of the rice pathogens Rhizoctonia solani and Pyricularia grisea, whereas 4% were pathogens identified as Burkholderia glumae, Burkholderia gladioli and Acidovorax avenae ssp. avenae.This study reveals a broad morphological and genetic diversity of bacteria present on seed of a single rice cultivar.This line of work contributes to a better understanding of the microbial diversity present on rice seed and stresses its importance as a carrier of antagonists and pathogens.

Pantoea

10.1111/j.1365-2672.2009.04268.x

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Citations (76)

Identification of QTLs conferring resistance to downy mildews of maize in Asia

Theoretical and Applied Genetics (2003)

M. L. C. George B. M. Prasanna R. S. Rathore T. A. S. Setty Firdaus Kasim

10.1007/s00122-003-1280-6

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Citations (71)

Perinatal transfer of genetic information: developing an algorithm for reporting cystic fibrosis prenatal test results to the newborn screening program

Genetics in Medicine (2008)

Ellen S. Regalado E. Langfelder-Schwind Andrew D. Corwin Kenneth A. Pass

Medical record

Prenatal Care

Carrier testing

10.1097/gim.0b013e31818a3107

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Citations (2)

International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations

Circulation Cardiovascular Genetics (2016)

Guillaume Jondeau Jacques Ropers Ellen S. Regalado Alan C. Braverman Arturo Evangelista

Background— The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. Methods and Results— The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2 . Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. Conclusions— Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.

10.1161/circgenetics.116.001485

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Citations (174)

FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

Journal of Clinical Investigation (2016)

Shao-Qing Kuang Olga Medina-Martínez Dong-Chuan Guo Limin Gong Ellen S. Regalado

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3–/– mice with p53–/– mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

Thoracic aortic aneurysm

Thoracic aorta

10.1172/jci83778

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Citations (92)