Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia

Abstract

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.

Fig 1. Localization of SMARCAL1 mutations detected in 34 subjects with Schimke immuno-osseous dysplasia.

Legend: $\begin{array}{|c|}\hline \text{Tagged (black frame)}\\ \hline\end{array}$: recurrent mutations detected in at least three unrelated patients; Green font: novel mutations described for the first time in the current study. Reference sequence: ENST00000357276; NM_014140.

Fig 2. Age at attainment of ESKD in 34 patients with SMARCAL1 glomerulopathy vs. 156 cases of NPHS2-associated SRNS from PodoNet Registry [4].

Fig 3. Progressive growth failure in children with Schimke immuno-osseous dysplasia.

Fig 4. Patient survival (left) and ESKD-free survival rate (right) of patients with Schimke immunoosseous dysplasia diagnosed based on phenotype vs. patients diagnosed incidentally through SRNS-panel gene testing.

Patients who deceased before reaching ESKD were censored in the renal survival analysis.