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Pseudohypoaldosteronism Type 1 NGS Panel

Genes:
NR3C2;
SCNN1A;
SCNN1B;
SCNN1G

Syndrome Information

Clinical Description

PHA1 is a salt-wasting disease.  Symptoms can include poor weight gain, failure to thrive, vomiting or dehydration and onset is typically in the newborn period or infancy.  Laboratory findings can include hyponatremia, hyperkalemia, elevated plasma aldosterone, and elevated plasma renin activity or direct renin concentration.  Treatment is salt supplementation.

In autosomal recessive PHA1, salt wasting occurs in the kidneys, sweat glands, salivary glands and colon.  The disorder tends to be severe and lifelong.  Mild presentations of recessive PHA1 can mimic non-classic cystic fibrosis, with borderline sweat chloride concentrations and mild sinopulmonary symptoms.  Pancreatic insufficiency is not observed.   

In dominant PHA1, salt wasting occurs only in the kidneys (it is sometimes referred to as renal PHA).  Many children outgrow the disorder and are able to stop treatment in early childhood.  Some adults have no childhood history of salt wasting and are only subclinically affected (elevated aldosteronism), so a negative family history is not necessarily sufficient to exclude the dominant form of PHA from the differential diagnosis.     

Inheritance Pattern

Autosomal Dominant with variable penetrance (NR3C2) (see Special Considerations)
Autosomal Recessive (SCNN1ASCNN1BSCNN1G)

Genotype-Phenotype Correlation

Symptoms of dominant PHA1 caused by NR3C2 mutations tend to improve with age until patients become essentially asymptomatic.  Adults who have mutations may have only elevated aldosterone and no history of illness; therefore, parental testing of an affected child is recommended to determine recurrence risk.  An intercurrent illness and resulting volume depletion in infants may be necessary for expression of renal PHA1; but heterogeneity has also been postulated.   

Test Information

Test Method

Next Generation Sequencing (NGS) of the coding regions and intron-exon boundaries of the listed genesDeletion/Duplication:  Dosage analysis by normalization of NGS read depth for the listed genes; Sanger sequencing for potential fill in / confirmation  

Clinical Utility

Identification of causative mutations in known or highly suspicious cases of PHA1; distinction between PHA1 subtypes for risk assessment and prognostic information; rule-out inherited causes of salt-wasting; targeted testing of relatives of proband; predictive prenatal testing when familial mutation is known.  

Clinical Sensitivity

58% of patients with a clinical diagnosis of PHA type 1 and 75% of patients with a clinical diagnosis and dominant family history of PHA type 1 have been reported to have a putative pathogenic NR3C2 mutation.  Deletions/duplications represented 18% of mutations in one published series of cases.  Recessive PHA1 is rare, and series of patients have not been published. In published cases, about 50% of causative mutations are identified in SCNN1A with the remainder equally split between SCNN1B and SCNN1G.  Up to 6% of SCNN1A mutations were deletions/duplications in one series.  There have been individual case reports of deletions/duplications in SCNN1B and SCNN1G, but no published case series.

Analytic Sensitivity

> 99% for inherited single nucleotide and small insertion/deletion variants for the nucleotides evaluated; >99% for multi-exon deletions and >98% for single exon deletions; >90% for multi-exon duplications and >75% for single exon duplications. Lower limit of detection for single nucleotide variants: 25% allele frequency (>99% sensitivity).

Sample Requirements

3-6ml whole blood in EDTA (purple topped) tubes. (see Pediatric or Adult blood sample algorithms for additional information)

We prefer whole blood for all tests.

Turn Around Time

Approximately 4 weeks

Fee and CPT Codes

$2600 for routine testing on a blood sample
CPT Codes: 81406 x 3, 81479

Please contact the lab to arrange testing for known mutations on blood or prenatal samples. 

Special Considerations

Adults who have NR3C2 mutations may have only elevated aldosterone and no history of illness; therefore, parental testing of an affected child is recommended to determine recurrence risk.  An intercurrent illness and resulting volume depletion in infants may be necessary for expression of renal PHA1; but heterogeneity has also been postulated.     

INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.