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.

Chair and Department of Pediatrics SMDZ in Zabrze Medical University of Silesia in Katowice Zabrze Poland

Department of Biology and Medical Genetics Clinical Genetics Unit Medical University of Gdansk Gdansk Poland

Department of Genetics Necker Hospital Assistance Publique Hôpitaux de Paris Paris France

Department of Molecular and Cellular Biology Intercollegiate Faculty of Biotechnology University of Gdańsk Gdańsk Poland

Department of Nephrology Kidney Transplantation and Hypertension The Children's Memorial Health Institute Warsaw Poland

Department of Pediatric Nephrology and Hypertension Dialysis Unit Jagiellonian University Medical College Krakow Poland

Department of Pediatric Nephrology Charité Universitätsmedizin Berlin Charité Children's Hospital Berlin Germany

Department of Pediatric Nephrology Cukurova University Adana Turkey

Department of Pediatric Nephrology Hacettepe University Faculty of Medicine Ankara Turkey

Department of Pediatric Nephrology Lublin Medical University Lublin Poland

Department of Pediatric Nephrology Pediatrics and Oncology Center Chorzów Poland

Department of Pediatric Nephrology University Children's Hospital Cologne Germany

Department of Pediatrics School of Medicine University of Jordan Amman Jordan

Department of Pediatrics University Hospital Motol Prague Czech Republic

Division of Pediatric Nephrology Center for Pediatrics and Adolescent Medicine University of Heidelberg Heidelberg Germany

Hacettepe University Center for Biobanking and Genomics Ankara Turkey

Inserm U1163 Imagine Institute Paris Descartes University Paris France

Nephrogenetics Laboratory Department of Pediatric Nephrology Hacettepe University Faculty of Medicine Ankara Turkey

Nephrology and Dialysis Unit Pediatric Subspecialties Department Bambino Gesú Children's Hospital IRCCS Rome Italy

Pediatric Kidney Liver and Metabolic Disease MHH Children´s Hospital Hannover Germany

Pediatric Nephrology Center of Excellence Pediatrics Department Faculty of Medicine King Abdulaziz University Jeddah Kingdom of Saudi Arabia

Pediatric Nephrology Necker Hospital Assistance Publique Hôpitaux de Paris Paris France

Pediatric Nephrology Unit Department of Pediatrics Bordeaux University Hospital Bordeaux France

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Schimke immunoosseous dysplasia: an ultra-rare disease. a 20-year case series from the tertiary hospital in the Czech Republic