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Abstract: FR-PO440

Trigenic COL4A3/COL4A4/COL4A5 Pathogenic Variants in Alport Syndrome: A Case Report

Session Information

  • Pediatric Nephrology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Rao, Dipti, Radboudumc, Nijmegen, Gelderland, Netherlands
  • Maas, Rutger J., Radboudumc, Nijmegen, Gelderland, Netherlands
  • Cornelissen, Elisabeth A.M., Radboudumc, Nijmegen, Gelderland, Netherlands
  • Wetzels, Jack F., Radboudumc, Nijmegen, Gelderland, Netherlands
  • van Geel, Michel, Maastricht Universitair Medisch Centrum+, Maastricht, Limburg, Netherlands
Introduction

Alport syndrome (AS) is a hereditary autosomal recessive (semi-dominant) or X-linked disorder of type IV collagen caused by mutations in COL4A3, COL4A4 and/or X-linked COL4A5. In recent years several cases of digenic AS, caused by two pathogenic variants in two COL4A genes, were reported. Patients with digenic AS may present with an atypical phenotype, depending on the percentage affected type IV trimeric collagen chain and inheritance advice may differ. We report a newly discovered case of trigenic AS.

Case Description

The female index patient, aged 51 years, was diagnosed with hematuria at age 24 yr, developed hypertension by the age of 30, and had pre-eclampsia and nephrotic syndrome during pregnancy at the age of 36. Post pregnancy proteinuria decreased to levels between 0.5 – 1.5 g/day with an ACE inhibitor. eGFR decreased initially, but has been stable in the past 5 years with eGFR 44ml/min/1.73m2. The patient wears hearing aids due to symmetric high tone sensorineural hearing loss. Her son was diagnosed with hypertension at 10 years old, attributed to the use of methylfenidate. He has minimal proteinuria and hematuria with normal eGFR. The 74-year-old mother is known with hypertension, hematuria and microalbuminuria. eGFR has been stable at 84ml/min/1.73m2. The father died at the age of 48 years, he was not known with a renal disorder or hearing loss. Because AS was suspected, genetic analysis in the index patient was performed. Two heterozygous pathogenic variants were detected: c.2691del in COL4A3 and c.1663dup in COL4A4. Furthermore, a complete heterozygous deletion of COL4A5 was detected, expanding beyond exon 1-4 of flanking COL4A6. Her son carried only the COL4A3 mutation, and the mother the COL4A4 mutation, confirming the familial autosomal mutations are present in trans. We presume the COL4A5 deletion has occurred de novo since the father had no clinical symptoms.

Discussion

We describe the first patient with Alport syndrome caused by three pathogenic mutations in all three COL4A genes, thus trigenic AS. The moderate phenotype in the female patient could be the result of residual functional type IV trimeric collagen. This case report emphasizes the importance of examining all three COL4A genes for optimal follow-up and treatment of the patient and adequate genetic counseling of family members.