Background:
Hypertension is a common condition in adults; however, hypertension in childhood is much less common and more likely due to an underlying genetic disorder. More specifically, monogenic hypertension refers to specific genetic mutations that interfere with renal and adrenal regulation of blood pressure.
Monogenic hypertension should be considered when a child presents with abnormal potassium levels in the presence of suppressed renin secretion and metabolic alkalosis or acidosis. Monogenic hypertension demonstrates three mechanisms of disease each causing a unique set of genetic disorders. The first mechanism involves gain-of-function mutations that cause hyperactivity of renal sodium and chloride reabsorption leading to plasma volume expansion. Examples include Liddle syndrome and Gordon syndrome (pseudohypoaldosteronism). The second mechanism involves deficiencies of enzymes that regulate adrenal steroid hormone synthesis and deactivation. Examples include congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. And, the third mechanism involves excess aldosterone synthesis that escapes normal regulatory mechanisms that lead to volumedependent hypertension with suppressed renin. Examples glucocorticoid-remediable aldosteronism.
All forms of monogenic hypertension lead to volume expansion and are associated with low renin, and electrolyte imbalance is highly suggestive of disease. Identifying a genetic form of monogenic hypertension can significantly alter clinical management and reduce morbidity and mortality.
The results from genetic tests can facilitate assessment of levels of risk for patients and lead to more efficient and appropriate medical management. It is recommended that this testing be accompanied by a complete family history and genetic counseling.
Reasons for Referral:
- Molecular confirmation of a clinical diagnosis of monogenic hypertension.
- To aid in decision-making for treatment and management of individuals with monogenic hypertension.
- Testing for individuals with a positive family history for monogenic hypertension (targeted testing is available if familial mutation is known).
Methodology:
Next generation sequencing will analyze the exons or coding regions of 16 monogenic hypertension-associated genes using Illumina NextSeq 500/550 technology. Samples are prepared using hybridization probes to enrich exonic regions. This assay does not assess regions of insufficient coverage, introns and promoter regions; pseudogenes; where the reference genome is inaccurate or contains gaps and insertions; and regions of high GC or polynucleotide repeats, but may contain variants that impact gene function.
Exon-level deletion/duplication analysis is performed by running the NGS data through the Genome Analysis Toolkit (GATK) Germline Copy Number Variation best practices pipeline from GATK, version 4.1.4.1. A Bayesian model was validated clinically in our lab. The model can detect copy changes at a resolution of three (3) or more probe targets (exons) for deletions and duplications in genes that do not have pseudogenes, and is not designed to detect low-level mosaicism or balanced alterations.
The 16 monogenic hypertension-associated genes are listed below:
CACNA1H, CLCN2, CUL3, CYP11B1, CYP11B2, CYP17A1, HSD11B2, KCNJ5, KLHL3, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1, WNK4
Specimen Requirements:
Blood: EDTA or ACD (Solution A or B):
- Adult: 5 mL
- Child: 5 mL
- Infant: 2-3 mL
Saliva: 2 ORAgene™ Saliva Collection Kit(s) (OGR-500) used according to manufacturer instructions. Please contact KDL Client Services for a Saliva Collection Kit for patients that cannot provide a blood sample.
Assisted Saliva: 4 ORAgene™ Saliva Collection Kit(s) (OGR-575) used according to manufacturer instructions. Please contact KDL Client Services for a Saliva Collection Kit for patients that cannot provide a blood sample.
Skin Fibroblast: Punch Biopsy (Cell cultures will be prepared at KDL and used for testing), or 2 T-25 confluent flasks
Prenatal:
- Direct Amniotic Fluid (10-20mL)
- Direct CVS
- Direct POC
- Cultured Amniocytes (2 T-25 flasks)
- Cultured CVS (2 T-25 flasks)
- Cultured fetal tissue: Product of Conception (2 T-25 flasks)
- Cord Blood (1-2mL)
DNA: 10µg at a minimum of 60-100ng/µL (DNA must be extracted in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or CMS)
Notice Regarding Molecular Genetic Testing on CVS or Amniotic Fluid Specimens:
- Maternal cell rule-out testing will be performed on all prenatal specimens received. Please provide maternal blood in addition to the fetal specimen. Additional charges apply for the maternal cell rule-out test.
For routine testing of blood, saliva and buccal swabs, KDL does NOT accept samples from patients within two (2) weeks of a packed cell/platelet transfusion or within four (4) weeks of a whole blood transfusion. For extraordinary circumstances, where testing must be performed outside of the above windows, please contact our lab.
A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES. Please include detailed clinical information, including ethnicity, clinical history, and family history.
Test Performed (Days):
Weekly
Turn Around Time:
6-8 weeks
Shipment Sensitivity Requirements:
- Package and ship specimen to remain cold, but not frozen.
- Ship via overnight express, using the FedEx priority overnight label provided.
- Contact Client Services for shipping kits and instructions at (855) 535- 1522.
References:
- Raina R, Krishnappa V, Das A, et al. Overview of Monogenic or Mendelian Forms of Hypertension. Front Pediatr. 2019;7:263. Published 2019 Jul 1. doi:10.3389/fped.2019.00263
- Simonetti GD, Mohaupt MG, Bianchetti MG. Monogenic forms of hypertension. Eur J Pediatr. 2012;171(10):1433-1439. doi:10.1007/s00431-011-1440-7
Additional Info: