P147: Identifying pathogenic FH variants in a healthcare-based cohort demonstrates associated phenotypes may be less common than previously estimated

Introduction: Alport syndrome (AS) is a genetically heterogeneous disorder caused by pathogenic variants in the type IV collagen genes (COL4A3, COL4A4, and COL4A5), which encode the α3, α4, and α5 chains of type IV collagen-a critical structural component of basement membranes in the kidney, cochlea, and eye.Clinically, AS is characterized by hematuria, proteinuria, chronic kidney disease, hearing loss, and ocular abnormalities.Historically, Xlinked AS, caused by pathogenic variants in COL4A5, has been considered the most common form, accounting for more than 70% of cases, followed by autosomal recessive AS resulting from homozygous or compound heterozygous pathogenic variants in COL4A3 or COL4A4.Autosomal dominant AS, caused by heterozygous variants in COL4A3 or COL4A4, was previously regarded as rare.However, with advances in genomic testing and increasing clinical recognition, a broader spectrum of AS presentations-including those identified outside traditional nephrology settings-is now being recognized.This study aims to define the clinical and genetic spectrum, as well as the contemporary diagnostic landscape, of AS in a tertiary specialized renal genetics clinic.Methods: A cohort of patients evaluated at the Cleveland Clinic Renal Genetics Clinic between January 2019 and October 2025 with a genetically confirmed diagnosis of Alport syndrome (pathogenic or likely pathogenic COL4A3-COL4A5 variant) were consented and enrolled in this study.All genetic testing was performed in CLIA-certified laboratories.Clinical and laboratory data were obtained through retrospective chart review, and statistical analyses were conducted using JMP version 8.0.Results: Ninety-seven patients were analyzed, including 37 males and 60 females, with a mean age of 36 years at index visit (interquartile range [IQR], 29-54).Patients were referred to the Renal Genetics Clinic from multiple specialties, including adult nephrology (46.4%), primary care (20.6%), pediatric nephrology (10.3%), prenatal genetics clinic (9.4%), and otolaryngology (1.0%).At the time of the index visit, renal manifestations were present in most patients: 78.9% had hematuria and 49% had proteinuria, with a median eGFR of 86.5 mL/min/1.73m 2 [44, 112.3].Kidney cysts were noted in 35.1%.Alportrelated extrarenal manifestations were less common, including bilateral sensorineural hearing loss (13.4%) and ocular abnormalities (11.3%).Among female participants, 6 (10%) had a history of preeclampsia.A family history of kidney disease was reported in 85 patients (87.6%), and 52 (53.6%) had a known family history of AS.Positive genetic findings were obtained through a variety of testing modalities, including broad kidney gene panels (44.8%), targeted variant testing (26.0%),AS-specific panels (18.8%), prenatal carrier screening (9.4%), and exome sequencing (1.0%).Genetic testing revealed that 32% had X-linked Alport syndrome, 65% had autosomal dominant AS, 1% had autosomal recessive AS, and 2.1% had digenic AS.Compared with male patients with X-linked AS, male patients with autosomal dominant AS were less likely to exhibit extrarenal manifestations (8.7% vs 38.5%, p=0.04).Females with autosomal dominant and X-linked AS exhibited similar rates of extrarenal involvement (17.9% vs 16.7%). Conclusion:This study is the real-world characterization of the Alport syndrome spectrum in a specialized renal genetics clinic.Our findings demonstrate an increasing number of referrals from prenatal genetics and primary care clinics, with a predominance of autosomal dominant Alport syndrome, which is associated with fewer extrarenal manifestations.Kidney cysts and preeclampsia appear to be relatively common among affected individuals.These results provide valuable insights to inform genetic counseling, clinical management, and multidisciplinary care strategies for patients with Alport syndrome.