Schimke immunoosseous dysplasia: Suggestions of genetic diversity

J. Marietta Clewing, Helen Fryssira, David Goodman, Sarah F. Smithson, Emily A. Sloan, Shu Lou, Yan Huang, Kunho Choi, Thomas Lücke, Harika Alpay, Jean Luc André, Yumi Asakura, Nathalie Biebuyck-Gouge, Radovan Bogdanovic, Dominique Bonneau, Caterina Cancrini, Pierre Cochat, Sandra Cockfield, Laure Collard, Isabel CordeiroValerie Cormier-Daire, Karlien Cransberg, Karel Cutka, Georges Deschenes, Jochen H H Ehrich, Stefan Fründ, Helen Georgaki, Encarna Guillen-Navarro, Barbara Hinkelmann, Maria Kanariou, Belde Kasap, Sara Sebnem Kilic, Guiliana Lama, Petra Lamfers, Chantal Loirat, Silvia Majore, David Milford, Denis Morin, Nihal Özdemir, Bertram F. Pontz, Willem Proesmans, Stavroula Psoni, Herbert Reichenbach, Silke Reif, Cristina Rusu, Jorge M. Saraiva, Onur Sakallioglu, Beate Schmidt, Lawrence Shoemaker, Sabine Sigaudy, Graham Smith, Flora Sotsiou, Natasa Stajic, Anja Stein, Asbjørg Stray-Pedersen, Doris Taha, Sophie Taque, Jane Tizard, Michel Tsimaratos, Newton A C S Wong, Cornelius F. Boerkoel

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCALl mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Original languageEnglish (US)
Pages (from-to)273-283
Number of pages11
JournalHuman Mutation
Issue number3
StatePublished - Mar 2007


  • Genocopy
  • Immunodeficiency
  • Locus heterogeneity
  • Proteinuria
  • Skeletal dysplasia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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