Familial Hypocalciuric Hypercalcemia — a benign condition that mimics primary hyperparathyroidism, where molecular CASR diagnosis prevents the unnecessary parathyroid surgery that FHH patients are frequently subjected to.
Whole genome sequencing identifies all CASR variants — distinguishing FHH (no surgery needed) from primary hyperparathyroidism (surgery curative) — the single test that prevents unnecessary operations in patients with hypercalcemia.
Familial Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant condition caused by heterozygous inactivating variants in CASR (calcium-sensing receptor, chromosome 3q13.33) — the receptor that detects serum calcium levels and regulates PTH secretion and renal calcium excretion. CASR haploinsufficiency shifts the calcium setpoint upward: the parathyroid glands interpret normal calcium as 'low' and maintain PTH secretion, producing mild-to-moderate hypercalcemia with inappropriately normal or mildly elevated PTH — a biochemical profile indistinguishable from primary hyperparathyroidism (PHPT).
FHH affects approximately 1 in 10,000-50,000 people and is almost always asymptomatic — the hypercalcemia is benign and does not cause the nephrolithiasis, osteoporosis, or neurocognitive symptoms seen in PHPT. The critical diagnostic feature is relative hypocalciuria: FHH patients have calcium-to-creatinine clearance ratio (CCCR) <0.01, while PHPT patients typically have CCCR >0.02. However, there is significant overlap in the 0.01-0.02 range, and many patients with FHH are misdiagnosed as PHPT and referred for parathyroidectomy.
Parathyroidectomy does NOT correct hypercalcemia in FHH — because the abnormality is in the calcium-sensing receptor, not the parathyroid gland. FHH patients who undergo parathyroidectomy remain hypercalcemic, may undergo re-exploration (with additional surgical risk), and may eventually have total parathyroidectomy causing permanent hypoparathyroidism requiring lifelong calcium and calcitriol replacement. This entirely preventable surgical harm occurs when FHH is not considered in the differential of hypercalcemia with elevated PTH. Molecular CASR genotyping provides the definitive distinction.
Homozygous CASR inactivation causes neonatal severe hyperparathyroidism (NSHPT) — a neonatal emergency requiring urgent total parathyroidectomy. FHH parents should be identified before pregnancy to assess NSHPT risk in offspring of two carriers.
FHH is misdiagnosed as primary hyperparathyroidism in up to 10% of surgical series. Molecular CASR testing prevents unnecessary parathyroidectomy—one of the clearest examples of genotype-guided surgical decision-making.
Parathyroidectomy does not fix FHH — molecular diagnosis prevents surgery that cannot help and may cause hypoparathyroidism
In surgical series, approximately 5-10% of patients referred for parathyroidectomy actually have FHH rather than PHPT. These patients undergo surgery that does not correct their hypercalcemia — because the calcium setpoint abnormality is in CASR, not the parathyroid glands. Failed first surgery may lead to re-exploration, and ultimately total parathyroidectomy causing permanent hypoparathyroidism. CASR genotyping before surgery identifies FHH patients, preventing this entirely avoidable iatrogenic harm. Whole genome sequencing provides CASR evaluation alongside comprehensive genomic analysis.
Calcium-to-creatinine clearance ratio has a gray zone of 0.01-0.02 — only molecular testing provides a definitive answer in equivocal cases
The CCCR cutoff of <0.01 for FHH and >0.02 for PHPT leaves a substantial gray zone where biochemistry cannot distinguish the two conditions. Factors affecting urinary calcium (vitamin D status, dietary calcium, renal function, diuretic use) further confound the CCCR calculation. In a patient with mild hypercalcemia, borderline PTH, and a CCCR in the equivocal range, molecular CASR genotyping provides the definitive diagnosis — FHH (no surgery) vs. PHPT (surgery curative). This single test resolves diagnostic ambiguity that would otherwise lead to either inappropriate surgery or unnecessary surveillance.
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Common questions about whole genome sequencing.
What is the difference between whole genome sequencing and a targeted genetic test?
Targeted genetic tests — including standard hereditary cancer panels — read a pre-defined list of known variants in a specific set of genes. They are designed to find what they already know to look for. Whole genome sequencing reads your entire genome: all 6 billion base pairs, every gene, every region between genes. A Mayo Clinic study published in JAMA Oncology found that standard testing guidelines missed more than half of patients with inherited cancer mutations. Genome Test does not have a fixed list.
What will I receive when my results are ready?
Your Dante Genome delivers 200+ physician-ready reports organized by clinical category — hereditary cancer, cardiac conditions, rare diseases, pharmacogenomics, carrier status, and more. Reports are delivered to your secure Genome Manager and are formatted for direct clinical use. Your genome data is permanently retained and re-analyzed automatically as science advances.
What happens if a clinically significant variant is found?
If a pathogenic or likely-pathogenic variant is identified, it will be clearly flagged in your physician-ready report with clinical context, published evidence, and recommended next steps. We recommend sharing any clinically significant finding with your physician or a genetic counselor, who can guide decisions about surveillance, risk reduction, or cascade testing for family members.
How is this different from a consumer DNA test like 23andMe or AncestryDNA?
Consumer DNA tests use genotyping chips that read less than 0.1% of your genome — a tiny pre-selected set of common variants. They are optimized for ancestry and population-level traits, not clinical genetic findings. The Dante Genome Test sequences 100% of your genome at 30X coverage, the same standard used in clinical diagnostic settings. The two tests are not comparable in scope, methodology, or clinical utility.
How long does it take to get results, and how are they delivered?
Your collection kit ships within 48 hours of ordering. Once your sample arrives at our CLIA-certified laboratory, sequencing and analysis takes 6–8 weeks. Results are delivered securely to your Genome Manager, where you can access your reports, share them with your physician, and receive automatic updates as new findings are validated against your genome.
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