Molecular Genetics Monogenic Hypertension Panel

Hypertension is one of the most prevalent diseases in the world , with an estimated 34% of individuals at or above the age of 20 in the United States (US) affected (Benjamin et al. 2018). 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 variants that interfere with normal renal and adrenal regulation of blood pressure (Raina et al. 2019). Monogenic hypertension should be considered when diagnosing hypertension in children, as the younger the child, the more likely the hypertension is due to a secondary cause. 

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. The third mechanism involves excess aldosterone synthesis that escapes normal regulatory mechanisms that lead to volume-dependent hypertension with suppressed renin (ex. glucocorticoid-remediable aldosteronism). Overall,  monogenic hypertension should be strongly considered when a child presents with abnormal potassium levels in the presence of suppressed renin secretion and metabolic alkalosis or acidosis. 

Identifying a genetic form of monogenic hypertension can significantly alter clinical management and reduce morbidity and mortality.  The results from genetic tests can facilitate risk assessment 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.

The genes included in this panel were curated in collaboration with clinical geneticists and nephrology experts from Doernbecher Children’s Hospital (DCH) (Pediatric Nephology) and the OHSU Division of Nephrology and Hypertension. The Pediatric Nephrology team at DCH specializes in the diagnosis and comprehensive care of infants, children and adolescents with kidney and urinary tract disorders. For clinical consultation with the Pediatric Nephrology team at DCH, please call 503-346-0640 or visit their website for further information. For adult patients, OHSU’s Nephrology and Hypertension Clinic offers a full range of clinical services, emphasizing a holistic, patient-centered model of care for patients with high blood pressure and chronic kidney disease. For a clinical consultation with OHSU’s Nephrology and Hypertension team, please call 503-494-3442 or visit the OHSU Nephrology and Hypertension Clinic website for further information.

Reasons for Referral:

• Molecular confirmation of a clinical diagnosis of monogenic hypertension.
• To aid in decision-making for treatment and management of individuals with suspected monogenic hypertension.
• Testing for individuals with a positive family history for monogenic hypertension (targeted testing is available if familial mutation is known).

Genomic DNA is analyzed using next-generation sequencing (NGS) on the Illumina NextSeq 2000 platform, with target enrichment performed using hybridization-based probes to capture exonic (coding) regions of the gene(s). Single nucleotide variants (SNVs) and small insertions or deletions (INDELs) are identified using the Illumina DRAGEN Enrichment Workflow, executed onboard the NextSeq2000. This pipeline combines software and hardware acceleration to generate high-confidence germline haplotype calls. Clinical and analytical validation of DRAGEN was performed in our laboratory. Based on validation study results, for SNVs, this assay achieves >96% analytical sensitivity and >99% positive predictive value (PPV). For INDELs <50 bp, the analytical sensitivity is >87% and the PPV is >97%. INDELs >50 bp may be detected but the sensitivity for these is reduced.

Exon-level copy number variants (CNVs) are detected using the Germline Copy Number Variation Best Practices pipeline from GATK. A Bayesian model, clinically validated in our laboratory, enables detection of deletions and duplications involving three or more contiguous exons in genes with adequate probe coverage and without complicating factors (e.g. pseudogene homology, short tandem repeats, segmental duplications). Please note that exon-centric microarray remains the gold standard for exonic copy number variant calling. If exon-centric microarray is of interest, please contact the laboratory for additional information.

This test is not designed to detect polynucleotide repeats, low-level mosaicism, structural rearrangements or balanced alterations (e.g. inversions, gene conversion events, translocations, etc.) or variants in difficult regions. Additionally, variants located in regions of insufficient coverage, including introns and promoter regions; pseudogenes; where the reference genome is inaccurate or contains gaps and insertions; and of high GC content may not be detected. This test does not provide complete coverage of all exons and noncoding regions may have limited information and ability to interpret. Variants in introns that are greater than 10 bp from the intron-exon junction may be analyzed. Please contact the laboratory if interrogation of intronic sequence greater than 10 bp from the intron-exon boundary is desired. 

The 17 monogenic hypertension-associated genes are listed below:
CACNA1H, CLCN2, CUL3, CYP11B1*, CYP11B2*, CYP17A1, HSD11B2, KCNJ5, KLHL3, NR3C1, NR3C2, PDE3A, SCNN1A, SCNN1B, SCNN1G, WNK1, WNK4

*Due to the high homology between CYP11B1 and CYP11B2, some CVNs may not be identified with this testing method.

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.

Buccal Cells: 4 CytoSoft™ Cytology Brush (Medical Packaging CYB-1) used according to manufacturer instructions.  Please contact KDL Client Services for a Buccal Collection Kit for patients that cannot provide a blood sample. Please note that buccal samples may yield a limited amount of DNA, and additional specimens may be required for confirmatory or supplementary testing.

Skin Fibroblast: Punch Biopsy (Cell cultures will be prepared at KDL and used for testing), or 2 T-25 confluent flasks.

DNA: 5-6µg 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).

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)

Notice Regarding Molecular Genetic Testing on Prenatal Specimens:

Maternal cell rule-out testing will be performed on all prenatal specimens received. Please provide maternal blood (or saliva) in addition to the fetal specimen. Additional charges apply for the maternal cell rule-out test.

For routine testing of blood and saliva (or DNA extracted from them), 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 within 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.

Weekly

6-8 weeks

• 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.  

1. Gallegos, F. R., Delahunty, M. P., Hu, J., Yerigeri, S. B., Dev, V., Bhatt, G., & Raina, R. (2025). Decoding monogenic hypertension: A review of rare hypertension disorders. American Journal of Hypertension, 38(6), 333–351. https://doi.org/10.1093/ajh/hpaf005
2. Lu, Y.-T., Fan, P., Zhang, D., Zhang, Y., Meng, X., Zhang, Q.-Y., Zhao, L., Yang, K.-Q., & Zhou, X.-L. (2021). Overview of monogenic forms of hypertension combined with hypokalemia. Frontiers in Pediatrics, 8. https://doi.org/10.3389/fped.2020.543309
3. Precone V, Krasi G, Guerri G, et al. Monogenic hypertension. Acta Biomed. 2019;90(10-S):50-52. doi:10.23750/abm.v90i10-S.8759
4. Raina, R., Krishnappa, V., Das, A., Amin, H., Radhakrishnan, Y., Nair, N. R., & Kusumi, K. (2019). Overview of monogenic or mendelian forms of hypertension. Frontiers in Pediatrics, 7. https://doi.org/10.3389/fped.2019.00263
5. Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018;137(12):e67-e492. doi:10.1161/CIR.0000000000000558