@article {1019, title = {Association of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.}, journal = {Neurology}, volume = {96}, year = {2021}, month = {2021 03 30}, pages = {e1783-e1791}, abstract = {

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.

}, keywords = {Adenosine Triphosphatases, Adult, Age of Onset, Aortic Diseases, Arterial Occlusive Diseases, Child, Preschool, Female, Femoral Artery, Humans, Iliac Artery, Male, Moyamoya Disease, Mutation, Renal Artery Obstruction, Ubiquitin-Protein Ligases}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000011653}, author = {Pinard, Amelie and Fiander, Maximillian D J and Cecchi, Alana C and Rideout, Andrea L and Azouz, Mohamed and Fraser, Stuart M and McNeely, P Daniel and Walling, Simon and Novara, Sarah C and Hurst, Anna C E and Guo, Dongchuan and Parkash, Sandhya and Bamshad, Michael J and Nickerson, Deborah A and Vandersteen, Anthony M and Milewicz, Dianna M} } @article {684, title = {The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 02}, pages = {427-431}, abstract = {

PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

METHODS: Exome sequencing from 39 trios were analyzed.

RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

}, keywords = {Adult, Cell Cycle Proteins, Cerebrovascular Disorders, Child, Child, Preschool, Developmental Disabilities, DNA Helicases, Exome, Female, Genetic Predisposition to Disease, Humans, Intellectual Disability, Male, Methyltransferases, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Middle Aged, Moyamoya Disease, Mutation, Nuclear Proteins, Transcription Factors, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0639-2}, author = {Pinard, Amelie and Guey, St{\'e}phanie and Guo, Dongchuan and Cecchi, Alana C and Kharas, Natasha and Wallace, Stephanie and Regalado, Ellen S and Hostetler, Ellen M and Sharrief, Anjail Z and Bergametti, Fran{\c c}oise and Kossorotoff, Manoelle and Herv{\'e}, Dominique and Kraemer, Markus and Bamshad, Michael J and Nickerson, Deborah A and Smith, Edward R and Tournier-Lasserve, Elisabeth and Milewicz, Dianna M} } @article {809, title = {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.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 10}, pages = {e1406}, abstract = {

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.

}, keywords = {Adult, Aortic Aneurysm, Thoracic, Bicuspid Aortic Valve Disease, Female, GATA4 Transcription Factor, Gene Frequency, Humans, Male, Middle Aged, Mutation, Receptor, Notch1, Receptors, Cell Surface, Smad6 Protein}, issn = {2324-9269}, doi = {10.1002/mgg3.1406}, author = {Musfee, Fadi I and Guo, Dongchuan and Pinard, Am{\'e}lie C and Hostetler, Ellen M and Blue, Elizabeth E and Nickerson, Deborah A and Bamshad, Michael J and Milewicz, Dianna M and Prakash, Siddharth K} } @article {219, title = {RNF213 rare variants in an ethnically diverse population with Moyamoya disease.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Nov}, pages = {3200-7}, abstract = {

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.

METHODS: We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families.

RESULTS: RNF213 p.R4810K was identified in 56\% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6\% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29\% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant.

CONCLUSIONS: These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.

}, keywords = {Adenosine Triphosphatases, Adolescent, Adult, Child, Cohort Studies, Ethnic Groups, Female, Genetic Variation, Humans, Male, Moyamoya Disease, Population Surveillance, Ubiquitin-Protein Ligases, Young Adult}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.006244}, author = {Cecchi, Alana C and Guo, Dongchuan and Ren, Zhao and Flynn, Kelly and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Wang, Gao T and Regalado, Ellen S and Steinberg, Gary K and Shendure, Jay and Bamshad, Michael J and Grotta, James C and Nickerson, Deborah A and Pannu, Hariyadarshi and Milewicz, Dianna M} }