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

TitleWhole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.
Publication TypeJournal Article
Year of Publication2018
AuthorsWarejko, JK, Schueler, M, Vivante, A, Tan, W, Daga, A, Lawson, JA, Braun, DA, Shril, S, Amann, K, Somers, MJG, Rodig, NM, Baum, MA, Daouk, G, Traum, AZ, Kim, HBae, Vakili, K, Porras, D, Lock, J, Rivkin, MJ, Chaudry, G, Smoot, LB, Singh, MN, Smith, ER, Mane, SM, Lifton, RP, Stein, DR, Ferguson, MA, Hildebrandt, F
Date Published2018 04
KeywordsAdolescent, Aorta, Abdominal, Aortic Valve Stenosis, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Hypertension, Jagged-1 Protein, Male, Mutation, Neurofibromatoses, Neurofibromin 1, Pedigree, Syndrome, United States, Whole Exome Sequencing

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (, , , , and ). Ten of the 15 mutations have not previously been reported. This is the first report of , , or mutations in individuals with MAS. Mutations were detected in (6/15 families), (4/15 families), (3/15 families), and one family each for and Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

Alternate JournalHypertension
PubMed ID29483232
PubMed Central IDPMC5843550
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States