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Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.

Publication ,  Journal Article
Coleman, DM; Wang, Y; Yang, M-L; Hunker, KL; Birt, I; Bergin, IL; Li, JZ; Stanley, JC; Ganesh, SK
Published in: Hum Mol Genet
February 3, 2022

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

February 3, 2022

Volume

31

Issue

3

Start / End Page

334 / 346

Location

England

Related Subject Headings

  • Renal Artery Obstruction
  • Neurofibromatosis 1
  • Molecular Biology
  • Male
  • Hypertension, Renovascular
  • Humans
  • Genetics & Heredity
  • Female
  • Child
  • Aortic Coarctation
 

Citation

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Coleman, D. M., Wang, Y., Yang, M.-L., Hunker, K. L., Birt, I., Bergin, I. L., … Ganesh, S. K. (2022). Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1. Hum Mol Genet, 31(3), 334–346. https://doi.org/10.1093/hmg/ddab241
Coleman, Dawn M., Yu Wang, Min-Lee Yang, Kristina L. Hunker, Isabelle Birt, Ingrid L. Bergin, Jun Z. Li, James C. Stanley, and Santhi K. Ganesh. “Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.Hum Mol Genet 31, no. 3 (February 3, 2022): 334–46. https://doi.org/10.1093/hmg/ddab241.
Coleman DM, Wang Y, Yang M-L, Hunker KL, Birt I, Bergin IL, et al. Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1. Hum Mol Genet. 2022 Feb 3;31(3):334–46.
Coleman, Dawn M., et al. “Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.Hum Mol Genet, vol. 31, no. 3, Feb. 2022, pp. 334–46. Pubmed, doi:10.1093/hmg/ddab241.
Coleman DM, Wang Y, Yang M-L, Hunker KL, Birt I, Bergin IL, Li JZ, Stanley JC, Ganesh SK. Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1. Hum Mol Genet. 2022 Feb 3;31(3):334–346.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

February 3, 2022

Volume

31

Issue

3

Start / End Page

334 / 346

Location

England

Related Subject Headings

  • Renal Artery Obstruction
  • Neurofibromatosis 1
  • Molecular Biology
  • Male
  • Hypertension, Renovascular
  • Humans
  • Genetics & Heredity
  • Female
  • Child
  • Aortic Coarctation