title: Schimke immunoosseous dysplasia: suggestions of genetic diversity.
abstract: 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 SMARCAL1 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: J Marietta
authors.initials: JM
authors.lastname: Clewing
authors.forename: Helen
authors.initials: H
authors.lastname: Fryssira
authors.forename: David
authors.initials: D
authors.lastname: Goodman
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Smithson
authors.forename: Emily A
authors.initials: EA
authors.lastname: Sloan
authors.forename: Shu
authors.initials: S
authors.lastname: Lou
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Kunho
authors.initials: K
authors.lastname: Choi
authors.forename: Thomas
authors.initials: T
authors.lastname: Lücke
authors.forename: Harika
authors.initials: H
authors.lastname: Alpay
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: André
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.forename: Nathalie
authors.initials: N
authors.lastname: Biebuyck-Gouge
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.forename: Pierre
authors.initials: P
authors.lastname: Cochat
authors.forename: Sandra
authors.initials: S
authors.lastname: Cockfield
authors.forename: Laure
authors.initials: L
authors.lastname: Collard
authors.forename: Isabel
authors.initials: I
authors.lastname: Cordeiro
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Karlien
authors.initials: K
authors.lastname: Cransberg
authors.forename: Karel
authors.initials: K
authors.lastname: Cutka
authors.forename: Georges
authors.initials: G
authors.lastname: Deschenes
authors.forename: Jochen H H
authors.initials: JH
authors.lastname: Ehrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Fründ
authors.forename: Helen
authors.initials: H
authors.lastname: Georgaki
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillen-Navarro
authors.forename: Barbara
authors.initials: B
authors.lastname: Hinkelmann
authors.forename: Maria
authors.initials: M
authors.lastname: Kanariou
authors.forename: Belde
authors.initials: B
authors.lastname: Kasap
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.forename: Guiliana
authors.initials: G
authors.lastname: Lama
authors.forename: Petra
authors.initials: P
authors.lastname: Lamfers
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Silvia
authors.initials: S
authors.lastname: Majore
authors.forename: David
authors.initials: D
authors.lastname: Milford
authors.forename: Denis
authors.initials: D
authors.lastname: Morin
authors.forename: Nihal
authors.initials: N
authors.lastname: Ozdemir
authors.forename: Bertram F
authors.initials: BF
authors.lastname: Pontz
authors.forename: Willem
authors.initials: W
authors.lastname: Proesmans
authors.forename: Stavroula
authors.initials: S
authors.lastname: Psoni
authors.forename: Herbert
authors.initials: H
authors.lastname: Reichenbach
authors.forename: Silke
authors.initials: S
authors.lastname: Reif
authors.forename: Cristina
authors.initials: C
authors.lastname: Rusu
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Saraiva
authors.forename: Onur
authors.initials: O
authors.lastname: Sakallioglu
authors.forename: Beate
authors.initials: B
authors.lastname: Schmidt
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shoemaker
authors.forename: Sabine
authors.initials: S
authors.lastname: Sigaudy
authors.forename: Graham
authors.initials: G
authors.lastname: Smith
authors.forename: Flora
authors.initials: F
authors.lastname: Sotsiou
authors.forename: Natasa
authors.initials: N
authors.lastname: Stajic
authors.forename: Anja
authors.initials: A
authors.lastname: Stein
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.forename: Doris
authors.initials: D
authors.lastname: Taha
authors.forename: Sophie
authors.initials: S
authors.lastname: Taque
authors.forename: Jane
authors.initials: J
authors.lastname: Tizard
authors.forename: Michel
authors.initials: M
authors.lastname: Tsimaratos
authors.forename: Newton A C S
authors.initials: NA
authors.lastname: Wong
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype
chemical_list: C412482:SMARCAL1 protein, human; D004265:DNA Helicases