The Phenotypic Spectrum of Heterozygotes.

INTRODUCTION

The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied.

METHODS

Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined ADAS, we matched heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis.

RESULTS

heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure ( < 0.05 for all comparisons) but not bilateral sensorineural hearing loss ( = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg ( = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs ( = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system.

CONCLUSION

This study demonstrates a wide spectrum of phenotypic severity in ADAS due to with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.