Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome

Warejko, Jillian K.; Schueler, Markus; Vivante, Asaf; Tan, Weizhen; Daga, Ankana; Lawson, Jennifer A.; Braun, Daniela A.; Shril, Shirlee; Amann, Kassaundra; Somers, Michael J.; Rodig, Nancy; Baum, Michelle A.; Daouk, Ghaleb H.; Traum, Avram Z.; Kim, Heung Bae; Vakili, Khashayar; Porras, Diego; Lock, James E.; Rivkin, Michael J.; Smoot, Leslie; Singh, Michael; Smith, Edward R.; Mane, Shrikant; Lifton, Richard P.; Stein, Deborah R.; Ferguson, Michael; Hildebrandt, Friedhelm

doi:10.1161/hypertensionaha.117.10296

Cited by 26 publications

(20 citation statements)

References 36 publications

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“…Whole-exome sequencing studies revealed that protein truncating mutations (splice site and frameshift mutations) in NF1 may result in MAS. 16 …”

Section: Discussionmentioning

confidence: 99%

“…NF1 is the most common genetic disorder associated with MAS and encountered for 5–22% of the cases. 1 , 3 , 6 , 7 , 16 , 17 , 19 Another study found NF1 as the second cause of MAS after Williams syndrome. 3 …”

Section: Discussionmentioning

confidence: 99%

“… 8–15 A recent study has been demonstrated that monogenic cause of MAS was present in 43% of 35 families with MAS and whole-exome sequencing revealed mutations in genes previously associated with vascular disease ( NF1, JAG1, ELN, GATA6, RNF213 ). 16 The prevalence of genetic diseases associated with MAS in different studies is presented in Table 2 .…”

Section: Introductionmentioning

confidence: 99%

“… 16 The prevalence of genetic diseases associated with MAS in different studies is presented in Table 2 .…”

Section: Introductionmentioning

confidence: 99%

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Diagnosis and Management of Genetic Causes of Middle Aortic Syndrome in Children: A Comprehensive Literature Review

Lazea¹,

Alkhzouz²,

Sufana³

et al. 2022

TCRM

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Middle aortic syndrome (MAS) is a rare vascular disease representing an important cause of severe hypertension in children. MAS is characterized by segmental or diffuse narrowing of the abdominal and/or distal descending aorta with involvement of the renal and visceral branches. Most cases of MAS are idiopathic, but MAS may occur in genetic and acquired disorders. The most common genetic causes of MAS are neurofibromatosis type I, Williams syndrome, Alagille syndrome, tuberous sclerosis and mucopolysaccharidosis. This review article discusses the pathophysiological aspects, distinctive associated features, and management of genetic forms of MAS in children.

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“…Whole-exome sequencing studies revealed that protein truncating mutations (splice site and frameshift mutations) in NF1 may result in MAS. 16 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“… 16 The prevalence of genetic diseases associated with MAS in different studies is presented in Table 2 .…”

Section: Introductionmentioning

confidence: 99%

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Diagnosis and Management of Genetic Causes of Middle Aortic Syndrome in Children: A Comprehensive Literature Review

Lazea¹,

Alkhzouz²,

Sufana³

et al. 2022

TCRM

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“…A recent study had characterized genetic contributors to the etiology of midaortic syndrome, reporting a genetic cause in almost half of children with midaortic syndrome. [10] We therefore hypothesized that there would also be a substantial genetic contribution to pediatric renovascular hypertension in general. We performed whole exome sequencing (WES) in our patient cohort, aiming to identify known causes as well as discover potentially novel ones.…”

Section: Introductionmentioning

confidence: 99%

Genetics of renovascular hypertension in children

Viering

Chan

Hoogenboom

et al. 2020

Journal of Hypertension

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Objective: In most cases of renovascular hypertension in children, the etiology is unclear. The aim of this study was to investigate genetic variation as a factor in the development of renovascular hypertension in children. Methods: In a cohort of 37 unrelated children from a single tertiary referral center, exome sequencing was performed. We assessed variants in recognized and suspected disease genes and searched for novel ones with a gene-based variantburden analysis. Results: In the majority of patients, exome sequencing could not identify causative variants. We found a pathogenic variant in a recognized associated disease gene in five patients (three pathogenic variants in NF1, one in ELN and a deletion of chromosome 7q11.23, consistent with Williams Syndrome). In two other patients, (likely) pathogenic variants were found in putative renovascular hypertension genes (SMAD6 and GLA), with clinical implications for both. Ten additional patients carried variants of uncertain significance (VUS) in known (n=4) or putative (n=6) renovascular hypertension disease genes. Rare variant burden analysis yielded no further candidate genes. Conclusions: Genetic contributors, such as germline mutations in NF1, ELN, 7q11.23del were present in only 5 out of 37 (14%) children with renovascular hypertension. Twelve other children (32%) had potentially causal variants identified, including a pathogenic variant in SMAD6; a vasculopathy gene hitherto unknown to link with renovascular hypertension. Most importantly, our data show that exome sequencing can rarely identify the cause of renovascular hypertension in nonsyndromic children. We suggest that non-genetic factors or somatic genetic variation will play a more important role.

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DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

et al. 2021

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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 PARTICIPANTSA genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016)(2017)(2018)(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. RESULTSOf 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...

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Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome

Cited by 26 publications

References 36 publications

Diagnosis and Management of Genetic Causes of Middle Aortic Syndrome in Children: A Comprehensive Literature Review

Diagnosis and Management of Genetic Causes of Middle Aortic Syndrome in Children: A Comprehensive Literature Review

Genetics of renovascular hypertension in children

DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

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