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

Beata S. Lipska-Ziętkiewicz , Jutta Gellermann , Olivia Boyer , Olivier Gribouval , Szymon Ziętkiewicz , Jaamela A. Kari , Mohamed A. Shalaby , Fatih Ozaltin , Jiri Dusek , Anette Melk , Aysun K. Bayazit , Laura Massella , Lidia Hyla-Klekot , Sandra Habbig , Astrid Godron , Maria Szczepańska , Beata Bieniaś , Dorota Drożdż , Rasha Odeh , Wioletta Jarmużek , Katarzyna Zachwieja , Agnes Trautmann , Corinne Antignac , Franz Schaefer


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 oli-gosymptomatic 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.
Author Beata S. Lipska-Ziętkiewicz
Beata S. Lipska-Ziętkiewicz,,
, Jutta Gellermann
Jutta Gellermann,,
, Olivia Boyer
Olivia Boyer,,
, Olivier Gribouval
Olivier Gribouval,,
, Szymon Ziętkiewicz (IFB/IB/DMCB)
Szymon Ziętkiewicz,,
- Department of Molecular and Cellular Biology
, Jaamela A. Kari
Jaamela A. Kari,,
, Mohamed A. Shalaby
Mohamed A. Shalaby,,
, Fatih Ozaltin
Fatih Ozaltin,,
, Jiri Dusek
Jiri Dusek,,
, Anette Melk
Anette Melk,,
et al.`
Journal seriesPLoS ONE, ISSN 1932-6203, (A 40 pkt)
Issue year2017
Publication size in sheets0.55
Article numbere0180926
ASJC Classification2700 General Medicine; 1100 General Agricultural and Biological Sciences; 1300 General Biochemistry, Genetics and Molecular Biology
URL http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180926&type=printable
Languageen angielski
Score (nominal)40
Score sourcejournalList
ScoreMinisterial score = 40.0, 15-06-2020, ArticleFromJournal
Publication indicators WoS Citations = 7.000; Scopus SNIP (Source Normalised Impact per Paper): 2017 = 1.111; WoS Impact Factor: 2017 = 2.766 (2) - 2017=3.352 (5)
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