Kidney Week

Abstract: FR-PO1014

Genetic Alterations in Familial Focal Segmental Glomerulosclerosis

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Caliskan, Yasar, Yale School of Medicine, Yale University, New Haven, United States

Yasar Caliskan,

• Besse, Whitney E., Yale School of Medicine, Yale University, New Haven, Connecticut, United States

Whitney E. Besse,

• Gulati, Ashima, Yale School of Medicine, Yale University, New Haven, Connecticut, United States

Ashima Gulati,

• Demir, Erol, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey

Erol Demir,

• Sever, Mehmet S., Istanbul School of Medicine, Istanbul University, Istanbul, Turkey

Mehmet S. Sever,

• Ishibe, Shuta, Yale School of Medicine, Yale University, New Haven, Connecticut, United States

Shuta Ishibe,

• Somlo, Stefan, Yale School of Medicine, Yale University, New Haven, Connecticut, United States

Stefan Somlo,

Background

The phenotypic variability observed in focal segmental glomerulosclerosis (FSGS) patients bearing mutations in the same gene suggests that modifier genes may impact renal presentation and outcomes. We investigated genetic alterations observed in inherited adult FSGS patients.

Methods

We analyzed 172 unrelated patients with biopsy proven idiopathic FSGS including familial (n=46) and non-familial (n=126) cases. Genetic sequencing, either whole exome sequencing (n=32) or a targeted gene panel (n=14), was performed on these 46 index patients with family history of kidney disease. Variants were included if: minor allele frequency <0.01 (recessive) or <0.001 (dominant); loss of function mutation or missense with CADD score ≥15; not seen as homozygotes in any control databases; amino acid residue conserved through evolution in multicellular organisms. Variant interpretation was done using the ACMG guideline.

Results

The median age of onset [29 (12-48) vs 35.5 (3-73) years] was significantly earlier in patients with familial FSGS compared to non-familial cases (p=0.004). The median follow up in months after diagnoses was similar between familial [38 (2-276)] and non-familial [42 (1-235)] cases (p=0.86). During follow-up, ESRD progression was higher in familial cases (21/46, 45.7%) compared with non-familial cases (22/126, 17.5%) (p<0.001). We identified a pathogenic genotype in 26 out of 46 familial cases. Thirteen individuals were explained by heterozygous (7/46, 15%) or homozygous/hemizygous/compound heterozygous (6/46, 13%) collagen IV gene (COL4) mutations. Thirteen individuals (13/46, 28%) were explained by mutations in the documented or recently proposed FSGS genes with or without a concurrent COL4 mutation [NPHS2 hom (n=2), NPHS2 hom/COL4A5 hem (n=1), ADCK4 hom (n=2), NUP107 hom (n=1), SCARB2 hom (n=1), TRPC6 het (n=1), LMX1B het (n=1), ARHGAP24 het/COL4A3 het (n=1), ABCA6 hom/COL4A4 het (n=1), LAMA5 hom/COL4A4 het (n=1), PALLD hom/COL4A5 het (n=1)].

Conclusion

Collagen IV gene mutations explain a significant fraction of familial FSGS in our population. In a limited number of patients with parental consanguinity carrying pathogenic genotype in podocyte-related genes, COL4 mutations were also found. Further analysis of the phenotype in patients with this co-inheritance could shed light on variations in phenotype in familial FSGS.

Funding

• Other NIH Support