Schimke Immunoosseous Dysplasia via the SMARCAL1 Gene

Schimke immunoosseous dysplasia (SIOD; OMIM#242900) is a multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in disproportionate short stature, nephropathy, and immunodeficiency. Radiographic features of SED may include ovoid and mildly flattened vertebral bodies, shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of SIOD patients have T-cell deficiency that is associated with risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated (Baradaran-Heravi et al. GeneReviews 2011).

Schimke immunoosseous dysplasia (SIOD) is inherited in an autosomal recessive manner. SMARCAL1 is the only gene currently known to be associated with SIOD. SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1) encodes HARP, the SNF2-related protein, which participates in DNA-nucleosome restructuring (Boerkoel et al. Nat Genet 30:215-220, 2002). Variants in SMARCAL1 are predicted to cause loss of function in HARP, the deficiency of which leads to increased DNA damage and hypersensitivity to DNA-damaging agents (Bansbach et al. Genes Dev 23:2405–2414, 2009). The majority of reported variants are missense, splicing, and truncating variants. A gross deletion has been documented as well (Boerkoel et al, 2002). Multiple studies have shown that genotype does not predict disease severity or outcome (Bökenkamp et al. Pediatr Nephrol 20:1724–1728, 2005; Lücke et al. Am J Med Genet A 135:202–205, 2005; Dekel et al. Pediatr Res 63:398–403, 2008, Baradaran-Heravi et al. Hum Mol Genet 21: 2572-2587, 2012).

This test is predicted to detect disease variants in 50-60% of individuals with clinical features of SIOD (Clewing et al. Hum Mutat 28:273–283, 2007).

This test provides full coverage of all coding exons of the SMARCAL1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).