Publications by authors named "Dianna Milewicz"

215 Publications

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Radiol Cardiothorac Imaging 2021 Aug 22;3(4):e200496. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes. ©  2021 Jointly between the RSNA, the European Association for Cardio-Thoracic Surgery, The Society of Thoracic Surgeons, and the American Association for Thoracic Surgery. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. All rights reserved. Bicuspid Aortic Valve, Aortopathy, Nomenclature, Classification.
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http://dx.doi.org/10.1148/ryct.2021200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424700PMC
August 2021

Marfan syndrome.

Nat Rev Dis Primers 2021 Sep 2;7(1):64. Epub 2021 Sep 2.

Montalcino Aortic Consortium (MAC), Houston, TX, USA.

Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.
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http://dx.doi.org/10.1038/s41572-021-00298-7DOI Listing
September 2021

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.

PLoS Genet 2021 Jul 29;17(7):e1009679. Epub 2021 Jul 29.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.
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http://dx.doi.org/10.1371/journal.pgen.1009679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354477PMC
July 2021

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

J Thorac Cardiovasc Surg 2021 Sep 22;162(3):e383-e414. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1016/j.jtcvs.2021.06.019DOI Listing
September 2021

Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional, and research purposes.

J Thorac Cardiovasc Surg 2021 09 22;162(3):781-797. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada; aeCedars Sinai Heart Institute, Los Angeles, Calif; afDivision of Cardiology, Columbia University Irving Medical Center/NY Presbyterian Hospital, New York, NY.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1016/j.jtcvs.2021.05.008DOI Listing
September 2021

Summary: International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Ann Thorac Surg 2021 09 22;112(3):1005-1022. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.001DOI Listing
September 2021

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Ann Thorac Surg 2021 09 22;112(3):e203-e235. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.119DOI Listing
September 2021

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

Eur J Cardiothorac Surg 2021 Sep;60(3):448-476

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1093/ejcts/ezab038DOI Listing
September 2021

Summary: international consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

Eur J Cardiothorac Surg 2021 Sep;60(3):481-496

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1093/ejcts/ezab039DOI Listing
September 2021

Image-based patient-specific flow simulations are consistent with stroke in pediatric cerebrovascular disease.

Biomech Model Mechanobiol 2021 Jul 20. Epub 2021 Jul 20.

Translational Imaging Group, Texas Children's Hospital, Houston, TX, USA.

Moyamoya disease (MMD) is characterized by narrowing of the distal internal carotid artery and the circle of Willis (CoW) and leads to recurring ischemic and hemorrhagic stroke. A retrospective review of data from 50 pediatric MMD patients revealed that among the 24 who had a unilateral stroke and were surgically treated, 11 (45.8%) had a subsequent, contralateral stroke. There is no reliable way to predict these events. After a pilot study in Acta mice that have features of MMD, we hypothesized that local hemodynamics are predictive of contralateral strokes and sought to develop a patient-specific analysis framework to noninvasively assess this stroke risk. A pediatric MMD patient with an occlusion in the right middle cerebral artery and a right-sided stroke, who was surgically treated and then had a contralateral stroke, was selected for analysis. By using an unsteady Navier-Stokes solver within an isogeometric analysis framework, blood flow was simulated in the CoW model reconstructed from the patient's postoperative imaging data, and the results were compared with those from an age- and sex-matched control subject. A wall shear rate (WSR) > 60,000 s (about 12 × higher than the coagulation threshold of 5000 s and 9 × higher than control) was measured in the terminal left supraclinoid artery; its location coincided with that of the subsequent postsurgical left-sided stroke. A parametric study of disease progression revealed a strong correlation between the degree of vascular morphology altered by MMD and local hemodynamic environment. The results suggest that an occlusion in the CoW could lead to excessive contralateral WSRs, resulting in thromboembolic ischemic events, and that WSR could be a predictor of future stroke.
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http://dx.doi.org/10.1007/s10237-021-01495-9DOI Listing
July 2021

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Am J Hum Genet 2021 09 14;108(9):1578-1589. Epub 2021 Jul 14.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.016DOI Listing
September 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Aug;78(8):993-1003

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
August 2021

Risk of sudden cardiac death in EXOSC5-related disease.

Am J Med Genet A 2021 08 4;185(8):2532-2540. Epub 2021 Jun 4.

Department of Pediatrics, Division of Cardiology, Texas Children's Hospital, Houston, Texas, USA.

The RNA exosome is a multi-subunit complex involved in the processing, degradation, and regulated turnover of RNA. Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065) and short stature, hearing loss, retinitis pigmentosa, and distinctive facies (EXOSC2, MIM #617763). More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies. An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals. Here, we provide a detailed clinical and molecular characterization of two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination, with cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT) due to compound heterozygous variants in EXOSC5: (1) NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported) and (2) NM_020158.4:c.302C > A (p.Thr101Lys; novel variant). A review of the literature revealed an additional family with biallelic EXOSC5 variants and cardiac conduction abnormalities. These clinical and molecular data provide compelling evidence that cardiac conduction abnormalities and arrhythmias are part of the EXOSC5-related disease spectrum and argue for proactive screening due to potential risk of sudden cardiac death.
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http://dx.doi.org/10.1002/ajmg.a.62352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382094PMC
August 2021

In-hospital outcomes and long-term survival of women of childbearing age with aortic dissection: results from a single-center database.

J Vasc Surg 2021 Apr 20. Epub 2021 Apr 20.

Department of Cardiothoracic and Vascular Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, Tex. Electronic address:

Objective: In the present study, we defined the outcomes and effects of pregnancy in a cohort of women of childbearing age with acute aortic dissection (AAD).

Methods: We reviewed our database of AAD to identify all eligible female patients. Women aged <45 years were included. Data on pregnancy timing with respect to the occurrence of dissection, the demographic data, dissection extent, dissection treatment, dissection-related outcomes, overall maternal and fetal mortality, and genetic testing results were analyzed.

Results: A total of 62 women aged <45 years had presented to us with AAD from 1999 to 2017. Of the 62 women, 37 (60%) had had a history of pregnancy at AAD. Of these 37 patients, 10 (27%) had had a peripartum aortic dissection, defined as dissection during pregnancy or within 12 months postpartum. Of the 10 AADs, 5 were type A and 5 were type B. Three patients had presented with AAD during pregnancy (one in the second and two in the third trimester). Five patients (50%) had developed AAD in the immediate postpartum period (within 3 months) and two (20%) in the late postpartum period. For the immediate postpartum AADs (<3 months), four of the five patients delivered via cesarean section. Of these 10 peripartum AADs, 3 (30%) had occurred in patients with known Marfan syndrome. In-hospital mortality for those with peripartum AAD was 10% (1 of 10). Fetal mortality was 20% (2 of 10).

Conclusions: The frequency of aortic dissection in women of childbearing age at our institution was low. However, pregnancy might increase the risk of those young women genetically predisposed to dissection events. From these data, this risk appears to be greatest in the immediate postpartum period, even for those who undergo cesarean section. Close clinical and radiographic surveillance is required for all women with suspected aortopathy, especially in the third trimester and early postpartum period.
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http://dx.doi.org/10.1016/j.jvs.2021.03.028DOI Listing
April 2021

Update on the genetic risk for thoracic aortic aneurysms and acute aortic dissections: implications for clinical care.

J Cardiovasc Surg (Torino) 2021 Jun 18;62(3):203-210. Epub 2021 Mar 18.

McGovern Medical School, Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.

Genetic variation plays a significant role in predisposing individuals to thoracic aortic aneurysms and dissections. Advances in genomic research have led to the discovery of 11 genes validated to cause heritable thoracic aortic disease (HTAD). Identifying the pathogenic variants responsible for aortic disease in affected patients confers substantial clinical utility by establishing a definitive diagnosis to inform tailored treatment and management, and enables identification of at-risk relatives to prevent downstream morbidity and mortality. The availability and access to clinical genetic testing has improved dramatically such that genetic testing is considered an integral part of the clinical evaluation for patients with thoracic aortic disease. This review provides an update on our current understanding of the genetic basis of thoracic aortic disease, practical recommendations for genetic testing, and clinical implications.
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http://dx.doi.org/10.23736/S0021-9509.21.11816-6DOI Listing
June 2021

Association of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.

Neurology 2021 03 10;96(13):e1783-e1791. Epub 2021 Feb 10.

From the Department of Internal Medicine (A.P., A.C.C., M.A., D.G., D.M.M.), McGovern Medical School, University of Texas Health Science Center at Houston; Maritime Medical Genetics Service (A.L.R., S.P., M.A.V.), Division of Neurosurgery (M.D.J.F., P.D.M., S.W.) and Department of Pediatrics (M.A.V.), Division of Medical Genetics, Dalhousie University, IWK Health Centre Halifax, Nova Scotia Canada; Department of Pediatrics (S.C.N.), Division of Child Neurology, and Department of Genetics (A.C.E.H.), University of Alabama at Birmingham; Department of Pediatrics (M.J.B., A.M.V.), Division of Genetics Medicine and Department of Genome Sciences (M.J.B., D.A.N.), University of Washington, Seattle; and Department of Pediatrics (S.M.F.), Division of Child Neurology, University of Texas McGovern Medical School.

Objective: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.

Methods: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.

Results: We identified 3 novel rare de novo variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.

Conclusions: These results indicate a novel syndrome associated with rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.
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http://dx.doi.org/10.1212/WNL.0000000000011653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055312PMC
March 2021

The Dynamic and Multifaceted Nature of Cardiovascular Disease and Using Genetic Testing to Inform Clinical Care: An International Perspective.

Clin Chem 2021 01;67(1):33-40

Department of Clinical Biochemistry, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

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http://dx.doi.org/10.1093/clinchem/hvaa251DOI Listing
January 2021

Cerebrovascular Disease Progression in Patients With Arg179 Pathogenic Variants.

Neurology 2021 01 16;96(4):e538-e552. Epub 2020 Nov 16.

From the Departments of Neurology (A.L., S.L.S., P.L.M.) and Radiology (J.B.P., J.K.-K., P.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Internal Medicine (E.R., D.M.M.), McGovern Medical School, University of Texas Health Science Center at Houston; Department of Neuroradiology (A.L., M.C.), Goethe University, Frankfurt am Main, Germany; andDepartment of Neurosurgery (E.S.), Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objective: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with Arg179 pathogenic variants.

Methods: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury.

Results: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis.

Conclusions: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905785PMC
January 2021

Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development.

Arterioscler Thromb Vasc Biol 2020 12 15;40(12):e322-e335. Epub 2020 Oct 15.

Department of Integrative Biology and Pharmacology (W.G.R., F.C.M., W.Y., H.W., X.C.), McGovern Medical School, The University of Texas Health Science Center, Houston.

Objective: The cAMP second messenger system, a major stress-response pathway, plays essential roles in normal cardiovascular functions and in pathogenesis of heart diseases. Here, we test the hypothesis that the Epac1 (exchange protein directly activated by cAMP 1) acts as a major downstream effector of cAMP signaling to promote atherogenesis and represents a novel therapeutic target. Approach and Results: To ascertain Epac1's function in atherosclerosis development, a triple knockout mouse model () was generated by crossing mice with atherosclerosis-prone mice lacking both and . Deletion of Epac1 led to a significant reduction of atherosclerotic lesion formation as measured by postmortem staining, accompanied by attenuated macrophage/foam cell infiltrations within atherosclerotic plaques as determined by immunofluorescence staining in animals compared with littermates. Primary bone marrow-derived macrophages were isolated from Epac1-null and wild-type mice to investigate the role of Epac1 in lipid uptake and foam cell formation. ox-LDLs (oxidized low-density lipoproteins) stimulation of bone marrow-derived macrophages led to elevated intracellular cAMP and Epac1 levels, whereas an Epac-specific agonist, increased lipid accumulation in wild-type, but not Epac1-null, bone marrow-derived macrophages. Mechanistically, Epac1 acts through PKC (protein kinase C) to upregulate LOX-1 (ox-LDL receptor 1), a major scavenger receptor for ox-LDL uptake, exerting a feedforward mechanism with ox-LDL to increase lipid uptake and propel foam cell formation and atherogenesis.

Conclusions: Our study demonstrates a fundamental role of cAMP/Epac1 signaling in vascular remodeling by promoting ox-LDL uptake and foam cell formation during atherosclerosis lesion development. Therefore, Epac1 represents a promising, unexplored therapeutic target for atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.119.314238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831851PMC
December 2020

Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast-like Cells Is Driven by an Unfolded Protein Response.

Arterioscler Thromb Vasc Biol 2021 01 8;41(1):302-316. Epub 2020 Oct 8.

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX (A.C., C.S.K., K.K., A.K., J.C., D.M.M.).

Objective: Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents free cholesterol-induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin and thapsigargin, is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs.

Conclusions: Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.
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http://dx.doi.org/10.1161/ATVBAHA.120.315164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752246PMC
January 2021

Actin R256 Mono-methylation Is a Conserved Post-translational Modification Involved in Transcription.

Cell Rep 2020 09;32(13):108172

Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA. Electronic address:

Nuclear actin has been elusive due to the lack of knowledge about molecular mechanisms. From actin-containing chromatin remodeling complexes, we discovered an arginine mono-methylation mark on an evolutionarily conserved R256 residue of actin (R256me1). Actin R256 mutations in yeast affect nuclear functions and cause diseases in human. Interestingly, we show that an antibody specific for actin R256me1 preferentially stains nuclear actin over cytoplasmic actin in yeast, mouse, and human cells. We also show that actin R256me1 is regulated by protein arginine methyl transferase-5 (PRMT5) in HEK293 cells. A genome-wide survey of actin R256me1 mark provides a landscape for nuclear actin correlated with transcription. Further, gene expression and protein interaction studies uncover extensive correlations between actin R256me1 and active transcription. The discovery of actin R256me1 mark suggests a fundamental mechanism to distinguish nuclear actin from cytoplasmic actin through post-translational modification (PTM) and potentially implicates an actin PTM mark in transcription and human diseases.
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http://dx.doi.org/10.1016/j.celrep.2020.108172DOI Listing
September 2020

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

Genet Med 2021 01 28;23(1):111-122. Epub 2020 Aug 28.

Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France.

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD.

Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models.

Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4 mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4 mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.

Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
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http://dx.doi.org/10.1038/s41436-020-00947-4DOI Listing
January 2021

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.

Genet Med 2021 01 21;23(1):103-110. Epub 2020 Aug 21.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies.

Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2.

Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
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http://dx.doi.org/10.1038/s41436-020-00939-4DOI Listing
January 2021

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.

Mol Genet Genomic Med 2020 10 3;8(10):e1406. Epub 2020 Aug 3.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%-2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD.

Methods: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12% BAV, 29% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63% TAD, 34% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD.

Results: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p < .003).

Conclusion: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.
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http://dx.doi.org/10.1002/mgg3.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549564PMC
October 2020

TGFBR1 Rare Variant Associated With Thoracic Aortic Aneurysm, Double Chamber Left Ventricle, Coronary Anomaly, and Inducible Ventricular Tachycardia.

Circ Cardiovasc Imaging 2020 06;13(6):e010084

Division of Cardiology (K.B.-J., N.B.M., D.R., S.N., I.A.E., D.K., R.W.S., S.K.P.), Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285880PMC
June 2020

In Vitro Lineage-Specific Differentiation of Vascular Smooth Muscle Cells in Response to SMAD3 Deficiency: Implications for SMAD3-Related Thoracic Aortic Aneurysm.

Arterioscler Thromb Vasc Biol 2020 07 14;40(7):1651-1663. Epub 2020 May 14.

From the Department of Cardiac Surgery, North Campus Research Complex, University of Michigan, Ann Arbor (J.G., D.Z., L.J., P.Q., Y.E.C., B.Y.).

Objective: SMAD3 pathogenic variants are associated with the development of thoracic aortic aneurysms. We sought to determine the role of SMAD3 in lineage-specific vascular smooth muscle cells (VSMCs) differentiation and function. Approach and Results: c.652delA, a frameshift mutation and nonsense-mediated decay, was introduced in human-induced pluripotent stem cells using CRISPR-Cas9. The wild-type and (c.652delA) human-induced pluripotent stem cells were differentiated into cardiovascular progenitor cells or neural crest stem cells and then to lineage-specific VSMCs. Differentiation, contractility, extracellular matrix synthesis, and TGF-β (transforming growth factor-β) signaling of the differentiated VSMCs were analyzed. The homozygous frameshift mutation resulted in SMAD3 deficiency and was confirmed in human-induced pluripotent stem cells by Sanger sequencing and immunoblot analysis. In cardiovascular progenitor cell-VSMCs, SMAD3 deletion significantly disrupted canonical TGF-β signaling and decreased gene expression of VSMC markers, including SM α-actin, myosin heavy chain 11, calponin-1, SM22α, and key controlling factors, SRF and myocardin, but increased collagen expression. The loss of SMAD3 significantly decreased VSMC contractility. In neural crest stem cells-VSMCs, SMAD3 deficiency did not significantly affect the VSMC differentiation but decreased ELN (elastin) expression and increased phosphorylated SMAD2. Expression of mir-29 was increased in VSMCs, and inhibition of mir-29 partially rescued ELN expression.

Conclusions: SMAD3-dependent TGF-β signaling was essential for the differentiation of cardiovascular progenitor cell-VSMCs but not for the differentiation of neural crest stem cell-VSMCs. The lineage-specific TGF-β responses in human VSMCs may potentially contribute to the development of aortic root aneurysms in patients with mutations.
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http://dx.doi.org/10.1161/ATVBAHA.120.313033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316596PMC
July 2020

Targeting the NLRP3 Inflammasome With Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice.

J Am Heart Assoc 2020 04 30;9(7):e014044. Epub 2020 Mar 30.

Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX.

Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3)-caspase-1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic aneurysm and dissection induced by challenging wild-type mice with a high-fat, high-cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge-induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3-caspase-1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP-9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase-1 directly activated MMP-9 by cleaving its N-terminal inhibitory domain. Moreover, the genetic knockdown of or in mice or treatment of mice with MCC950 diminished the challenge-induced N-terminal cleavage of MMP-9, MMP-9 activation, and aortic destruction. Conclusions Our findings suggest that the NLRP3-caspase-1 inflammasome directly activates MMP-9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.
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http://dx.doi.org/10.1161/JAHA.119.014044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428617PMC
April 2020

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

Circulation 2020 01 30;141(1):42-66. Epub 2019 Dec 30.

Cardiovascular Research Institute (J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX.

Background: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.

Methods: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in -deficient () mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.

Results: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.

Conclusions: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939474PMC
January 2020

Do Variants Predispose to Thoracic Aortic Aneurysms and Dissections?

Circ Genom Precis Med 2019 12 15;12(12):e002626. Epub 2019 Nov 15.

Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center (H.L.H., E.S.R., D.-c.G., L.X., D.M.M.).

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http://dx.doi.org/10.1161/CIRCGEN.119.002626DOI Listing
December 2019

Grange syndrome due to homozygous YY1AP1 missense rare variants.

Am J Med Genet A 2019 12 21;179(12):2500-2505. Epub 2019 Oct 21.

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houstan, Texas.

Grange syndrome (OMIM 602531) is an autosomal recessive condition characterized by severe early onset vascular occlusive disease and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene. We report on the case of a 53-year old female with novel homozygous missense variants in YYA1P1 (c.1079C>T, p.Pro360Leu), presenting with a history of brachysyndactyly, hypertension, and ischemic stroke. Imaging studies revealed stenosis of the bilateral internal carotid with extensive collateralization of cerebral vessels in a moyamoya-like pattern, along with stenosis in the splenic, common hepatic, celiac, left renal, and superior mesenteric arteries. Functional studies conducted with the patient's dermal fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein. This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility.
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http://dx.doi.org/10.1002/ajmg.a.61379DOI Listing
December 2019
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