Publications by authors named "Rocio Moran"

32 Publications

Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.

Mol Genet Genomic Med 2021 Mar 5:e1647. Epub 2021 Mar 5.

Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.

Background: Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role.

Methods And Results: By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants. Targeted next generation sequencing analysis confirmed the deletion and showed that it was part of a complex local genomic rearrangement. In addition, we also detected a 648 Kb de novo deletion in an isolated BHC case. Both deletions are located downstream from NKX2-1 on chromosome 14q13.2-q13.3 and share a 33 Kb smallest region of overlap with six previously reported cases. This region has no gene but contains multiple evolutionarily highly conserved non-coding sequences.

Conclusion: We propose that the deletion of potential regulatory elements necessary for NKX2-1 expression in this critical region is responsible for BHC phenotype in these patients, and this is a novel disease-causing mechanism for BHC.
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http://dx.doi.org/10.1002/mgg3.1647DOI Listing
March 2021

Cutis marmorata telangiectatica congenita: a focus on its diagnosis, ophthalmic anomalies, and possible etiologic factors.

Ophthalmic Genet 2020 04 31;41(2):101-107. Epub 2020 Mar 31.

Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder typified by localized or generalized cutaneous vascular anomalies, which dissipate over time. We review the diagnostic approach to CMTC and present a comprehensive examination of its ocular manifestations. Additionally, we offer recommendations for the ophthalmologic workup for patients with CMTC. Finally, we examine the possible causes of CMTC and summarize the current efforts to establish an etiologic mechanism for this disease. Thirty-three published cases of CMTC with ocular anomalies are examined in detail. CMTC is diagnosed based on a specific set of congenital cutaneous symptoms, principally congenital reticular erythema that is unresponsive to local warming and absence of venectasia within the skin lesions. Ocular findings are not currently employed in this diagnostic process, likely due to an incomplete understanding into their presentation, frequency, and natural history. We show that the majority of ophthalmic manifestations are congenital, with glaucoma and posterior segment anomalies, consisting of retinal perfusion defects and vascular abnormalities, as the most frequently reported findings. Typical ophthalmic medical and surgical interventions appear to be effective for management of these CMTC-related pathology. Unfortunately, the etiology and pathophysiology of CMTC remains unknown, which obfuscates efforts to identify, examine, and initiate treatment in patients. While the ophthalmic community has traditionally viewed glaucoma as the classic ocular anomaly of CMTC, this dataset advocates for the prompt investigation of posterior segment abnormalities as well. However, our understanding of CMTC's ocular anomalies is complicated by a lack of reporting and/or incomplete (or nonexistent) ophthalmic examinations, and we strongly encourage comprehensive ophthalmic examinations for all CMTC patients at the time of diagnosis, followed by appropriate screening and surveillance throughout life. We believe these recommendations will spur additional data and disease insights that may be useful for future refinements to CMTC diagnostic algorithms.
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http://dx.doi.org/10.1080/13816810.2020.1744018DOI Listing
April 2020

Genetics of syndromic and nonsyndromic aortopathies.

Curr Opin Pediatr 2019 12;31(6):694-701

Division of Genetics and Genomics, The MetroHealth System, Cleveland, Ohio, USA.

Purpose Of Review: To review the literature and provide a summary of management of syndromic and nonsyndromic aortopathies.

Recent Findings: The number of newly identified genetic causes for aortopathies have continued to increase over the past 10 years. The number of reported individuals with most hereditary aneurysm genes is small but increasing with more publications focusing describing the natural history caused by each gene.

Summary: Aortopathy can present as an isolated finding or present as part of a larger genetic syndrome. Advances in genetic testing technology has shed light on the increasing importance of molecular diagnostics in the evaluation and management of patients with hereditary aortic disease. Molecular diagnostics and family phenotyping can aide in the diagnosis and management of pediatric patients with aortic disease.
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http://dx.doi.org/10.1097/MOP.0000000000000836DOI Listing
December 2019

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.

Genet Med 2019 08 25;21(8):1797-1807. Epub 2019 Jan 25.

CHU Nantes, Service de Génétique Médicale, Nantes, France.

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.

Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.

Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.

Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
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http://dx.doi.org/10.1038/s41436-019-0433-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752677PMC
August 2019

Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care.

Clin Transl Sci 2018 01 27;11(1):71-76. Epub 2017 Jul 27.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients' wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The percent of patients with a predicted phenotype associated with a gene-based CPIC dosing recommendation was determined. Ninety-nine patients (93.4%) elected to receive secondary pharmacogenomic findings. For each gene-drug pair analyzed, the number of patients with an actionable phenotype ranged from two (2%) to 43 patients (43.4%). Combining all gene-drug pairs, 84 unique patients (84.8%) had an actionable phenotype. A prospective multidisciplinary practice model was developed for integrating secondary pharmacogenomic findings into clinical practice. Our model highlights a unique collaboration between physician-geneticists, pharmacists, and genetic counselors.
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http://dx.doi.org/10.1111/cts.12493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759733PMC
January 2018

LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

Circ Res 2016 Mar 12;118(6):928-34. Epub 2016 Jan 12.

From the Departments of Internal Medicine (D.G., E.S.R., L.G., X.D., Z.R., B.C., E.M.H., D.M.M.) and Cardiothoracic and Vascular Surgery (A.E., H.J.S.), University of Texas Health Science Center, Houston; Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L.); Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat, Paris, France (P.A., G.J., C.B.); Centre National de Référence pour le syndrome de Marfan et apparentés, Département de Génétique Moléculaire, AP-HP, Hôpital Bichat, Paris, France (P.A., C.B.); Department of Pediatrics, MetroHealth Medical Center, Cleveland, OH (R.M.); Department of Medicine, Stanford University Medical Center, CA (D.L.); and Department of Genome Sciences, University of Washington, Seattle (M.J.B., J.S., D.A.N.).

Rationale: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families.

Objectives: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections.

Methods And Results: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections.

Conclusions: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.307130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839295PMC
March 2016

Evolving Approaches to Genetic Evaluation of Specific Cardiomyopathies.

Curr Heart Fail Rep 2015 Dec;12(6):339-49

Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA.

The understanding of the genetic basis of cardiomyopathy has expanded significantly over the past 2 decades. The increasing availability, shortening diagnostic time, and lowering costs of genetic testing have provided researchers and physicians with the opportunity to identify the underlying genetic determinants for thousands of genetic disorders, including inherited cardiomyopathies, in effort to improve patient morbidities and mortality. As such, genetic testing has advanced from basic scientific research to clinical application and has been incorporated as part of patient evaluations for suspected inherited cardiomyopathies. Genetic evaluation framework of inherited cardiomyopathies typically encompasses careful evaluation of family history, genetic counseling, clinical screening of family members, and if appropriate, molecular genetic testing. This review summarizes the genetics, current guideline recommendations, and evidence supporting the genetic evaluation framework of five hereditary forms of cardiomyopathy: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), and left ventricular noncompaction (LVNC).
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http://dx.doi.org/10.1007/s11897-015-0271-7DOI Listing
December 2015

USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.

Mol Cell 2015 Sep 10;59(6):956-69. Epub 2015 Sep 10.

Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.
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http://dx.doi.org/10.1016/j.molcel.2015.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575888PMC
September 2015

Granulomatous disease associated with NOD2 sequence variants and familial camptodactyly: An intermediate form of NOD2-associated diseases?

Semin Arthritis Rheum 2015 Dec 21;45(3):357-60. Epub 2015 May 21.

Department of Rheumatic and Immunologic Disease/A50, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195; Division of Rheumatology, Allergy and Immunology, Stony Brook University, Stony Brook, NY. Electronic address:

Objective: Nucleotide-binding oligomerization domain-containing protein-2 (NOD2)-associated diseases may be a spectrum of disease. We report two families who exhibited an intermediate form of Blau syndrome and NOD2-associated autoinflammatory disease (NAID).

Methods: We identified two families with granulomatous disease. The clinical phenotypes and genotypes of these two families were reviewed and analyzed.

Results: The proband in family 1 was a white 57-year-old woman, with camptodactyly (age 6 years), inflammatory polyarthritis and dermatitis (age of 30 years), and cough, dyspnea, dry eyes, parotid gland enlargement, and fever. A computerized tomography showed mediastinal lymphadenopathy without hilar involvement, and a mediastinal lymph node biopsy revealed non-caseating granuloma. Pedigree analysis suggested autosomal dominant inheritance, and genetic testing identified a NOD2 sequence variant IVS8(+158). The proband in family 2 was a white 50-year-old woman with inflammatory polyarthritis and periarticular subcutaneous nodules. Skin biopsy showed non-necrotizing granuloma. There was a family history of camptodactyly, and genetic testing identified a NOD2 sequence variant R703C.

Conclusions: Both probands had granulomatous disease and autosomal dominant phenotype of familial camptodactyly coupled with the presence of the NOD2 sequence variants, IVS8(+158), and R703C. Granulomatous disease associated with NOD2 variants may be an intermediate form between Blau syndrome and NAID.
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http://dx.doi.org/10.1016/j.semarthrit.2015.05.007DOI Listing
December 2015

Systemic connective tissue features in women with fibromuscular dysplasia.

Vasc Med 2015 Oct 8;20(5):454-62. Epub 2015 Jul 8.

Cleveland Clinic Department of Cardiovascular Medicine, Cleveland, OH, USA

Fibromuscular dysplasia (FMD) is a non-atherosclerotic disease associated with hypertension, headache, dissection, stroke, and aneurysm. The etiology is unknown but hypothesized to involve genetic and environmental components. Previous studies suggest a possible overlap of FMD with other connective tissue diseases that present with dissections and aneurysms. The aim of this study was to investigate the prevalence of connective tissue physical features in FMD. A total of 142 FMD patients were consecutively enrolled at a single referral center (97.9% female, 92.1% of whom had multifocal FMD). Data are reported for 139 female patients. Moderately severe myopia (29.1%), high palate (33.1%), dental crowding (29.7%), and early-onset arthritis (15.6%) were prevalent features. Classic connective features such as hypertelorism, cleft palate, and hypermobility were uncommon. The frequency of systemic connective tissue features was compared between FMD patients with a high vascular risk profile (having had ⩾1 dissection and/or ⩾2 aneurysms) and those with a standard vascular risk profile. A history of spontaneous pneumothorax (5.9% high risk vs 0% standard risk) and atrophic scarring (17.6% high risk vs 6.8% standard risk) were significantly more prevalent in the high risk group, p<0.05. High palate was observed in 43.1% of the high risk group versus 27.3% in the standard risk group, p=0.055. In conclusion, in a cohort of women with FMD, there was a prevalence of moderately severe myopia, high palate, dental crowding, and early-onset osteoarthritis. However, a characteristic phenotype was not discovered. Several connective tissue features such as high palate and pneumothorax were more prominent among FMD patients with a high vascular risk profile.
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http://dx.doi.org/10.1177/1358863X15592192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840458PMC
October 2015

NOD2-associated autoinflammatory disease: a large cohort study.

Rheumatology (Oxford) 2015 Oct 11;54(10):1904-12. Epub 2015 Jun 11.

Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, OH, USA.

Objective: The aims of the study were to characterize the genotype profile of nucleotide-binding oligomerization domain containing 2 (NOD2)-associated autoinflammatory disease (NAID) and to report an extended study of the disease.

Methods: A total of 143 adult patients presented with clinical phenotypes suspicious for NAID and all were genotyped for NOD2 sequence variants. The genotype frequencies were compared between our cohort and literature reports. These patients were divided into two groups predicated on the presence or absence of NOD2 variants.

Results: Of the 143 patients, 67 (47%) carry NOD2 variants; the genotype frequency was significantly higher among our cohort than in the historical healthy controls. Fifty-four of the 67 carriers of NOD2 variants had NAID, which has a genotype profile that is somewhat different from Crohn's disease. All NAID patients were non-Jewish whites and 69% were women. The median age at onset was 33.5 years and the median disease duration at diagnosis was 10.7 years. NAID was sporadic in 93% of cases. Patients typically presented with periodic fever, dermatitis and inflammatory arthritis. As compared with the NOD2 variant-negative patients, the skin disease more typically manifested as erythematous patches or plaques on the trunk. Oligopolyarthritis/-arthralgia was common, with characteristic distal lower extremity swelling. Associated NOD2 variants were primarily IVS8(+158) or compound IVS8(+158) and R702W.

Conclusion: This study underscores the NOD2 genotype association with NAID, which is a genetically complex multisystem disorder. It differs phenotypically from Crohn's disease with a distinct genotype profile. This disease may be more common than initially thought.
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http://dx.doi.org/10.1093/rheumatology/kev207DOI Listing
October 2015

Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4.

Am J Med Genet A 2015 Aug 30;167A(8):1758-62. Epub 2015 Apr 30.

Pediatric Cardiology, Cleveland Clinic, Cleveland, Ohio.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFβ pathway. Other syndromes associated with abnormalities in TGFβ signaling include Marfan syndrome, Loeys-Dietz syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.
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http://dx.doi.org/10.1002/ajmg.a.37093DOI Listing
August 2015

Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations.

Circ Cardiovasc Genet 2015 Jun 10;8(3):457-64. Epub 2015 Mar 10.

Departments of Internal Medicine (E.S.R., D.G., S.P., T.A.B., K.F., D.M.M.), Cardiothoracic and Vascular Surgery (A.E., H.S.), University of Texas Health Science Center at Houston; Department of Medicine, Stanford University Medical Center, CA (D.L.); Connective Tissue Gene Tests, Allentown, PA (J.H.); Department of Cardiac and Vascular Sciences, St. George's, University of London, London, United Kingdom (A.C., G.A.); AP-HP, Hôpital Bichat, Centre National de Référence pour le syndrome de Marfan et apparentés, Paris, France (C.B., G.J.), Université Paris 7, Paris, France (C.B., G.J.), AP-HP, Hôpital Bichat, Laboratoire de Génétique moléculaire, Boulogne, France (C.B.), and INSERM, U1148, Paris, France (C.B., G.J.); AP-HP, Hôpital Bichat, Service de Cardiologie, Paris, France (G.J.); Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (A.B.); Genomic Medicine Institute, Cleveland Clinic, OH (R.M.); Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (T.M., H.M.); Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.P.); Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (J.C., S.L.); and Texas Heart Institute and Baylor St. Luke's Medical Center, Houston (J.C., S.L.).

Background: ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations.

Methods And Results: Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years versus 36 years). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta, and aortic arch. Overall, cumulative risk of an aortic event at age 85 years was 0.76 (95% confidence interval, 0.64-0.86). After adjustment for intrafamilial correlation, sex and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared with other mutations.

Conclusions: ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601641PMC
June 2015

MAT2A mutations predispose individuals to thoracic aortic aneurysms.

Am J Hum Genet 2015 Jan 31;96(1):170-7. Epub 2014 Dec 31.

Department of Internal Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address:

Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.
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http://dx.doi.org/10.1016/j.ajhg.2014.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289682PMC
January 2015

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.

Hum Mutat 2015 Jan 27;36(1):69-78. Epub 2014 Nov 27.

Biomedical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
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http://dx.doi.org/10.1002/humu.22709DOI Listing
January 2015

Family history of aortic disease predicts disease patterns and progression and is a significant influence on management strategies for patients and their relatives.

J Vasc Surg 2013 Sep 1;58(3):573-81. Epub 2013 Jul 1.

Department of Vascular Surgery, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Background: While a positive family history (FH) is a known risk factor for developing an aneurysm, its association with the extent of disease has not been established. We evaluated the influence of a FH of aortic disease with respect to the pattern and distribution of aortic aneurysms in a given patient.

Methods And Results: From November 1999 to November 2011, 1263 patients were enrolled in physician-sponsored endovascular device trials to treat aortic aneurysms. Of the 555 patients who were alive and returning for follow-up, we obtained 426 (77%) family histories. Three-dimensional imaging studies were used to identify the presence of aneurysms; 36% (155/426) of patients had a FH of aortic aneurysms and 5% (21/155) had isolated intracranial aneurysms. A logistic regression model was used to compare aortic morphology between patients with a positive or negative FH for aneurysms. Patients with a positive FH of aortic aneurysms were younger at their initial aneurysm (63 vs 70 years; P < .0001), more frequently had proximal aortic involvement (root: odds ratio [OR], 5.4; P < .0001; ascending: OR, 2.9; P < .001; thoracic: OR, 2.2; P = .01) with over 50% of FH patients ultimately developing suprarenal aortic involvement (P = .0001) and had a greater incidence of bilateral iliac artery aneurysm (OR, 1.8; P = .03).

Conclusions: FH is an important tool that provides insight into the expected behavior of the untreated aorta and has significant implications for the development of treatment strategies. These findings should be used to guide patient's management with regard to treatment, follow-up paradigms, genetic testing, and screening of other family members.
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http://dx.doi.org/10.1016/j.jvs.2013.02.239DOI Listing
September 2013

Treatment of a patient with vertebral and subclavian aneurysms in the setting of a TGFBR2 mutation.

J Vasc Surg 2013 Apr 9;57(4):1116-9. Epub 2013 Jan 9.

Department of Vascular and Endovascular Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA.

We present the case of a patient diagnosed with hypermobile Ehlers-Danlos syndrome with aneurysms of the subclavian and vertebral arteries. Molecular testing demonstrated transforming growth factor-beta receptor type 2 mutation. She was not a candidate for an open repair; therefore, a hybrid approach involving right vertebral ligation and bypass from the right common carotid to the vertebral C1-2 interface, endovascular exclusion of the left vertebral artery, and stent grafting of the left subclavian/axillary artery was used. The left vertebral embolization proved ineffective, requiring a right-to-left vertebral catheterization with glue occlusion. Based on her proper molecular diagnosis, she underwent prophylactic root and ascending aortic repair.
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http://dx.doi.org/10.1016/j.jvs.2012.09.067DOI Listing
April 2013

Midterm results of David reimplantation in patients with connective tissue disorder.

Ann Thorac Surg 2013 Feb 31;95(2):555-62. Epub 2012 Dec 31.

Marfan Syndrome and Connective Tissue Disorder Clinic, Cleveland, Ohio 44195, USA.

Background: Few series have examined follow-up risks of the David reimplantation operation in patients with connective tissue disorder. Hence, we assessed its midterm safety and effectiveness for Marfan syndrome and other connective tissue disorders, such as Ehlers-Danlos, Loeys-Dietz, and marfanoid syndromes.

Methods: Of 313 patients who underwent modified David reimplantation, 178 identified as having connective tissue disorders underwent operation from January 1, 1991, to December 31, 2010. These disorders included Marfan (84%), marfanoid (8.4%), Loeys-Dietz (5.6%), Ehlers-Danlos (1.1%), and other syndromes (1.1%). Concomitant procedures included mitral valve repair in 7.3% and an atrial fibrillation procedure in 3.4%.

Results: There were no operative or 30-day deaths. Complications included prolonged ventilation (3%), renal failure (3%), reoperation for bleeding (2.2%), and permanent stroke (0.56%). Eight-year survival was 94% and freedom from aortic valve reoperation at 6 years was 92%. Of the 7 aortic valve reoperations, 3 were attributable to endocarditis and 3 to technical failure. One reoperation was performed at another hospital, and the reason could not be determined. There were no late strokes or hemorrhagic events. At 4 years, approximately 70% of patients had no aortic valve regurgitation, and 18% were in grade 1+.

Conclusions: Prophylactic root and valve preservation using David reimplantation is safe and provides excellent midterm effectiveness and low risk of late events except for endocarditis.
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http://dx.doi.org/10.1016/j.athoracsur.2012.08.043DOI Listing
February 2013

Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia.

Vasc Med 2012 Dec 11;17(6):371-8. Epub 2012 Oct 11.

Cleveland Clinic Heart and Vascular Institute and the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.

Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-β receptor 1 and 2 (TGFβR1 and TGFβR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFβR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFβR1 gene, a finding which merits further investigation.
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http://dx.doi.org/10.1177/1358863X12459650DOI Listing
December 2012

Genetic counselors: your partners in clinical practice.

Cleve Clin J Med 2012 Aug;79(8):560-8

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

As our understanding of the human genome has grown, so too has the need for health care providers who can help patients and families understand the implications of these new discoveries for their health care. Increasingly, genetic counselors are working in partnership with physicians to provide a continuum of care from risk assessment to diagnosis. In this article, we explain the process of genetic counseling and its value for patients who have a personal or family history of a hereditary condition.
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http://dx.doi.org/10.3949/ccjm.79a.11091DOI Listing
August 2012

Neonatal stroke and progressive leukoencephalopathy in a child with an ACTA2 mutation.

J Child Neurol 2013 Apr 29;28(4):531-4. Epub 2012 Jun 29.

Center for Pediatric Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Mutations in the smooth muscle-specific isoform of α-actin (ACTA2) cause vascular smooth muscle dysfunction leading to aortic aneurysm and moyamoya syndrome. A unique R179H mutation in ACTA2 has been reported to result in widespread smooth muscle dysfunction affecting vascular and extravascular smooth muscles. We report a 7-year-old girl with an ACTA2 R179H mutation manifesting with neonatal seizures due to multifocal infarcts, asymmetric motor deficits, global developmental delay, spasticity, congenital bilateral mydriasis, and a large patent ductus arteriosus. Serial magnetic resonance imaging (MRI) of the brain over 7 years showed diffuse supratentorial white matter abnormalities consistent with a progressive leukoencephalopathy. Magnetic resonance angiography of the cerebral vessels showed stenosis in the terminal portion of the bilateral internal carotid arteries with fusiform dilation of the proximal segment. Neonatal onset of neurologic symptoms in ACTA2 mutations has not been previously reported. R179H mutation in ACTA2 represents the severe end of the disease spectrum.
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http://dx.doi.org/10.1177/0883073812446631DOI Listing
April 2013

Building an innovative model for personalized healthcare.

Cleve Clin J Med 2012 Apr;79 Suppl 1:S1-9

Center for Personalized Healthcare, Cleveland Clinic, 9500 Euclid Avenue, NE50, Cleveland, OH 44195, USA.

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http://dx.doi.org/10.3949/ccjm.79.s1.01DOI Listing
April 2012

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features.

Hum Mutat 2012 Apr;33(4):728-40

Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington 99207, USA.

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.
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http://dx.doi.org/10.1002/humu.22037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618980PMC
April 2012

Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I.

Am J Med Genet A 2012 Feb 13;158A(2):455-60. Epub 2012 Jan 13.

Cleveland Clinic Foundation, Genomic Medicine Institute, Cleveland, Ohio, USA.

We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected.
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http://dx.doi.org/10.1002/ajmg.a.34428DOI Listing
February 2012

Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25.

Am J Med Genet A 2011 Jun 5;155A(6):1336-51. Epub 2011 May 5.

Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, California, USA.

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.
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http://dx.doi.org/10.1002/ajmg.a.34049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109510PMC
June 2011

Impaired systolic function in Loeys-Dietz syndrome: a novel cardiomyopathy?

Circ Heart Fail 2009 Nov;2(6):707-8

Heart and Vascular Institute, Cardiology, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.888636DOI Listing
November 2009

Patient education and informed consent for preimplantation genetic diagnosis: health literacy for genetics and assisted reproductive technology.

Genet Med 2009 Sep;11(9):640-5

Department of Bioethics, Center for Genetic Research Ethics and Law, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Purpose: Innovative applications of genetic testing have emerged within the field of assisted reproductive technology through preimplantation genetic diagnosis. As in all forms of genetic testing, adequate genetic counseling and informed consent are critical. Despite the growing recognition of the role of informed consent in genetic testing, there is little data available about how this process occurs in the setting of preimplantation genetic diagnosis.

Methods: A cross-sectional study of in vitro fertilization clinics offering preimplantation genetic diagnosis in the United States was conducted to assess patient education and informed consent practices. Descriptive data were collected with a self-administered survey instrument.

Results: More than half of the clinics offering preimplantation genetic diagnosis required genetic counseling before preimplantation genetic diagnosis (56%). Genetic counseling was typically performed by certified genetic counselors (84%). Less than half (37%) of the clinics required a separate informed consent process for genetic testing of embryonic cells. At a majority of those clinics requiring a separate informed consent for genetic testing (54%), informed consent for preimplantation genetic diagnosis and genetic testing took place as a single event before beginning in vitro fertilization procedures.

Conclusions: The results suggest that patient education and informed consent practices for preimplantation genetic diagnosis have yet to be standardized. These findings warrant the establishment of professional guidelines for patient education and informed consent specific to embryonic genetic testing.
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http://dx.doi.org/10.1097/GIM.0b013e3181ac6b52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678738PMC
September 2009