Kidney Week

Abstract: SA-PO564

Whole Exome Sequencing Identifies a Monogenic Cause in ~43% of Families with Hypertension from Midaortic Syndrome

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Warejko, Jillian Kateri, Boston Children's Hospital , Boston, Massachusetts, United States

Jillian Kateri Warejko,

• Schueler, Markus, Boston Children's Hospital , Boston, Massachusetts, United States

Markus Schueler,

• Vivante, Asaf, Boston Children's Hospital , Boston, Massachusetts, United States

Asaf Vivante,

• Lawson, Jennifer A., Boston Children's Hospital , Boston, Massachusetts, United States

Jennifer A. Lawson,

• Tan, Weizhen, Boston Children's Hospital , Boston, Massachusetts, United States

Weizhen Tan,

• Daga, Ankana, Boston Children's Hospital , Boston, Massachusetts, United States

Ankana Daga,

• Shril, Shirlee, Boston Children's Hospital , Boston, Massachusetts, United States

Shirlee Shril,

• Mane, Shrikant M., Yale University, New Haven, Connecticut, United States

Shrikant M. Mane,

• Stein, Deborah R., Boston Children's Hospital , Boston, Massachusetts, United States

Deborah R. Stein,

• Ferguson, Michael A., Boston Children's Hospital , Boston, Massachusetts, United States

Michael A. Ferguson,

• Hildebrandt, Friedhelm, Boston Children's Hospital , Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Midaortic syndrome (MAS) is a cause of severe hypertension in children with narrowing of the abdominal aorta. It involves the renal vessels in >80% of cases (Ped Nephrol 24:2225, 2009). Treatment requires antihypertensive medications and operative or endovascular interventions. Morbidity is high with hypertensive encephalopathy, stroke, heart failure and renal dysfunction. MAS may occur as part of a genetic syndrome, such as neurofibromatosis 1. However, most cases have been considered idiopathic until now.

Methods

We hypothesized that in patients with MAS, a monogenic cause of disease may be detected in one of 38 candidate genes of syndromic or non-syndromic vasculopathies. We studied 36 individuals from 35 different families by whole exome sequencing (WES).

Results

Patients were recruited at Boston Children’s Hospital from 1/2014 to 12/ 2016. Individuals were included in WES if MAS was diagnosed before age <25 years with evidence of narrowing of the abdominal aorta on imaging. We examined WES data for mutations in all 38 candidate genes. In 15/35 families (42.9%), we identified a causative dominant or recessive mutation. Mutations were identified in five candidate genes: NF1 (6/15 families), JAG1 (4/15), ELN (3/15), and one each for GATA6 and RNF213. A total of 15 different mutations were detected, 10 of which were novel. In 2/6 families with NF1 mutation and 1/4 families with JAG1 mutation the appropriate diagnosis of NF or Alagille syndrome respectively, had not yet been made by clinical criteria.

Conclusion

We demonstrate that WES in combination with an a priori candidate gene approach can provide a conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. We present data that there may be genotype/phenotype correlations between the severity of the mutation and the phenotype observed.

Funding

• Other NIH Support