# Severe Renal Phenotype Across A Multigenerational Tuberous Sclerosis Complex (TSC) Family

## TL;DR

A family with a specific TSC2 gene mutation shows a severe kidney disease pattern, highlighting the link between genetic variants and clinical outcomes in Tuberous Sclerosis Complex.

## Contribution

This study identifies a genotype–phenotype correlation between a TSC2 variant and severe renal disease in a multigenerational family.

## Key findings

- A TSC2 nonsense variant (c.1372C>T; p.Arg458*) is associated with severe renal manifestations in multiple family members.
- Affected individuals developed large angiomyolipomas, renal cystic disease, and chronic kidney disease leading to renal failure.
- The case series supports the importance of genotype–phenotype correlations for clinical management in TSC.

## Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in the brain, kidney, and heart, along with other complex clinical manifestations, including TSC‐associated neuropsychiatric disorder (TAND). Development of genotype–phenotype correlations within TSC can aid clinicians in providing prognostic data and improve clinical management. We present here a multigenerational family who has a pathogenic variant in TSC2 displaying a severe renal phenotype.

A 23‐year‐old Caucasian male (Patient 1) was determined to have a molecularly confirmed diagnosis of TSC at approximately 2 months of age. The nonsense pathogenic variant (c.1372C>T (p.Arg458*)) in TSC2 had been previously identified in his father (Patient 6), grandmother (Patient 5), and other extended paternal family members (Patient 2, 3, 4, 7).

Clinical evaluations revealed that the affected family members display a severe renal phenotype characterized by large angiomyolipoma burden (AMLs), renal cystic disease, and chronic kidney disease leading to renal failure.

Our clinical report is of significance as it illustrates a possible genotype–phenotype correlation between a specific TSC2 pathogenic variant and a severe renal phenotype. Our case series highlights the importance of establishing genotype–phenotype interactions to provide anticipatory guidance using prognostic data and clinical management.

A five generation family with a known pathogenic variant (c.1372C>T; p.Arg458*) in TSC2 displaying a severe renal phenotype characterized by large angiomyolipomas, renal cystic disease, and chronic kidney disease leading to renal failure. Our report illustrates a possible genotype–phenotype and highlights the importance of establishing genotype–phenotypes for clinical management purposes.