A Family with Autosomal Dominant Alport Syndrome with Phenotypic Variability

Introduction: Alport syndrome (AS) is a glomerulopathy, characterized by glomerular hematuria, progressive hearing loss and ocular abnormalities. It is inherited in X-linked, Autosomal Dominant (AD) and Recessive (AR)manner. Mutations in COL4A3 are responsible for ADAS. Case Description: A 32 YO female with no past history was referred for microscopic hematuria/high blood pressure. She had microscopic hematuria with normal creatinine. Family history was significant for AS in her father who had been on dialysis since the age of 46 years. Father was diagnosed with AS based on a kidney biopsy showing features of AS, progressive hearing loss, lenticonus. Given normal renal function we decided to proceed with genetic testing to confirm AS instead of a kidney biopsy. Results revealed a heterozygous missense mutation in COL4A3 c.3955G>A (p.Gly1319Arg) which was reported as variant of uncertain significance(VUS). Her father was then tested and was found to have the same mutation. It was determined that despite it being reported as VUS it was likely causative of AS in both of them. Upon further history, multiple family members were on dialysis/had kidney disease including paternal and maternal uncle. While the Pt herself did not have any ocular or hearing abnormalities and preserved kidney fucntion, her father had all the classical symptoms by mid-30's. Discussion: Compared to X-linked and ARAS, ADAS is considered least severe with majority of pts having hematuria and only a few with CKD and needing dialysis. A study found that in ADAS there was no significant difference in males and females in term of kidney survival. Extra-renal features are rare in ADAS, but our Pt’s father had classical extra-renal features of lenticonus and early onset progressive sensorineural hearing loss. To the best of our knowledge till date this mutation has not be known to cause ADAS. The complexity of ADAS diagnosis and management is compounded by the broad range of phenotypic expressions observed in patients. In addition, individuals often exhibit a spectrum of symptoms, from severe to completely asymptomatic within families sharing the same genetic mutation. The absence of symptoms and preserved kidney function may suggest genetic modifiers, variable expressivity, incomplete penetrance, or the influence of other protective genetic or environmental factors.