Digenic Inheritance of Extracellular Matrix Mutations in a Family with FSGS

Background: Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases with different pathophysiologies and for which current diagnostic methods often fail to distinguish molecular mechanisms. We have recently reported whole exome sequencing (WES) in an adult FSGS cohort but most disease still remains unexplained. Methods: In an unexplained family with adult-onset autosomal dominant FSGS, WES was performed in 3 affected relatives to identify candidate genes. Results: The proband presented with proteinuria in his 20s and a renal biopsy at age 41 demonstrated FSGS (Figure 1). His two brothers also had FSGS documented in the 4th and 5th decades of life. The proband and his elder brother developed end-stage renal disease (ESRD) in the 5th decade of life while the youngest brother has stage 3b A3 CKD at age 59. Of the proband's 3 sisters, one developed proteinuria at the time of last followup at age 54. Her daughter whose renal biopsy also demonstrated FSGS at age 23, had approximately 3.3 g/d of proteinuria and an eGFR of 48 ml/min at age 30. After WES, five heterozygous rare variants were identified and sequenced in all affected relatives. Two of these variants segregated in affected family members and encoded extracellular mesangial matrix proteins. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. One of these genes is already reported to cause an autosomal recessive neurologic disorder.Figure 1.: (A) Pedigree of family FSGS15. Individuals with solid dot represents microalbuminuria. (B) Renal biopsy shows FSGS with a background of mild mesangial hypercellularity (PAS, 20x). Ultrastructural examination showed mild podocyte foot process effacement (2500x). ECM = extracellular matrixConclusions: We postulate that the additive effect of heterozygous mutations in extracellular matrix proteins leads to adult-onset FSGS. The absence of clinically significant extra-renal symptoms is likely as a result of the impact of the mutation which should lead to translated protein rather than complete deficiency seen in autosomal recessive disorders. Our results provide a signal of more complicated genetic inheritance patterns in unexplained families. Funding: Private Foundation Support, Government Support - Non-U.S.

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