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Kidney Week

Abstract: PO1992

Genetic Kidney Disease: The Importance of Variants of Uncertain Significance

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology


  • Gefen, Ashley M., Cohen Children's Medical Center, Queens, New York, United States
  • Castellanos, Laura J., Cohen Children's Medical Center, Queens, New York, United States
  • Singer, Pamela, Cohen Children's Medical Center, Queens, New York, United States
  • Basalely, Abby Miriam, Cohen Children's Medical Center, Queens, New York, United States
  • Sethna, Christine B., Cohen Children's Medical Center, Queens, New York, United States

Diagnosing genetic kidney disease has become more accessible with the advent of low-cost and rapid genetic testing. The Invitae nephrolithiasis (NL) panel performs next-generation sequencing to evaluate 35 genes associated with NL and nephrocalcinosis (NC).

Case Description

A 7-month-old, ex-full term, white female was referred to pediatric nephrology clinic for recurrent urinary tract infections (UTI). Review of systems was positive for nonbloody diarrhea. She had no allergies or pertinent family history. Vital signs were normal with height at 14th percentile and weight at 6th percentile. Physical exam was unremarkable. Kidney/bladder ultrasound showed bilateral medullary NC. Voiding cystourethrogram was normal. Laboratory evaluation showed hyponatremia (129 mmol/L), anion-gap metabolic acidosis, hypercalcemia (13.9 mg/dL, ionized calcium 1.52 mmol/L), hypophosphatemia (2.8 mg/dL), hypoparathyroidism (1.45 pg/mL), and hypercalciuria (urine calcium:creatinine 1.3 mg/mg). She was diagnosed with milk protein allergy with diarrhea and electrolyte derangements requiring supplementation. After the diarrhea resolved on milk-free formula, serum electrolytes normalized except for hypercalcemia. Hypercalciuria resolved with hydration and low sodium diet. All supplements were stopped except for potassium citrate. Invitae NL panel was sent and showed 2 heterozygous variants of uncertain significance (VUS) in gene SLC34A1. Mutations in SLC34A1 are associated with autosomal recessive (AR) infantile hypercalcemia 2 (IH2), autosomal dominant hypophosphatemic NL/osteoporosis, and AR Fanconi renotubular syndrome. Parental testing determined the VUS were in a trans-configuration. It was hypothesized that she may be a compound heterozygote for IH2, a disease associated with hypercalcemia, failure to thrive, dehydration, and NC. She was trialed on the treatment of IH2 (phosphorus supplementation) and within 1 week hypercalcemia resolved.


Although this patient had VUS in SLC34A1 rather than known pathogenic variants, her clinical presentation was consistent with IH2. Had IH2 treatment not been trialed, this patient would have had continue hypercalcemia with associated morbidity. This case illustrates how genetic testing may change clinical practice by altering treatment strategies, and the importance of taking VUS into consideration.