Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the <i>SMARCAL1</i> gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1-3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003-2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77-100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in <i>SMARCAL1</i> in 19 patients: <i>c.355_500del</i>, <i>c.2542G>T</i>, <i>c.2290C>T</i>, <i>c.2562del</i>, <i>c.2533_2534del</i>, <i>c.1582A>C</i>, <i>c.1933C>T</i>, <i>c.1010T>C</i>, <i>c.1736C>T</i>, <i>c.2070dup</i>, <i>c.2551A>T</i>, <i>c.2149_2150dup</i>, <i>c.939delC</i>, and <i>c.1451T>A</i>; the most common was <i>c.2542G>T</i>, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a "founder mutation" in Russia.