Abstract
Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extreme rarity. Here, we made a definitive SIOD diagnosis of a 5-year-old girl with an extremely mild phenotype by applying whole exome sequencing (WES). As a result, a novel maternal mutation (c.2141+5G > A) confirmed to create a novel splice donor site combined with a known paternal mutation (c.1933C > T; p.Arg645Cys) were detected. In addition, previous reported SIOD cases showed excessive enrichment for mutations in the helicase ATP-binding and C-terminal domains of SMARCAL1. Similarly, the novel mutation we identified caused a mutant protein truncated in the SMARCAL1 C-terminus. Interestingly, based on the phenotypic profile, compared to reported cases, the patient in our study exhibited milder symptoms with renal dysfunctions limited to asymptomatic proteinuria, but no neurological signs or recurrent infections. Moreover, we identified 73 SMARCAL1-interacting genes, which formed a significant interconnected interaction network with roles in disease-related pathways such as double-strand break repair via homologous recombination, DNA repair, and replication fork processing. Notably, the top 15 SMARCAL1-interacting genes all showed a similar renal temporal expression pattern. Altogether, to our knowledge, the case in this study is the first case diagnosed originally based on a genetic test via WES rather than a characteristic phenotype. The identification of the novel allelic mutation (c.2141+5G > A) extends the phenotypic spectrum of SMARCAL1 mutations and the following bioinformatics analysis presents additional genetic evidence to illustrate the role of SMARCAL1 in SIOD.
Highlights
Schimke immuno-osseous dysplasia (SIOD; OMIM #242900) is a rare autosomal recessive disorder with an estimated incidence of 1 in 3 million live births in the United States (Santangelo et al, 2014), which was first described by Schimke et al in 1971 (Schimke et al, 1971)
Schimke immuno-osseous dysplasia is a rare autosomal recessive disorder caused by compound mutations of SMARCAL (Boerkoel et al, 2002) characterized by dysmorphism (Saraiva et al, 1999; Boerkoel et al, 2000), spondyloepiphysial dysplasia (Spranger et al, 1991; Lucke et al, 2006), T cell immunodeficiency (Boerkoel et al, 2000; Lucke et al, 2006), and nephrotic syndrome (Boerkoel et al, 2000; Lucke et al, 2006)
From all of previously reported patients, we found that severe SIOD could arise from missense mutations, while frameshift and truncation mutations could lead to a mild phenotype, further suggesting that the genotype–phenotype correlations remain largely unpredictable (Elizondo et al, 2009)
Summary
Schimke immuno-osseous dysplasia (SIOD; OMIM #242900) is a rare autosomal recessive disorder with an estimated incidence of 1 in 3 million live births in the United States (Santangelo et al, 2014), which was first described by Schimke et al in 1971 (Schimke et al, 1971). Hypothyroidism, bone marrow failure, and episodic cerebral ischemia have been reported in some severely affected patients (Boerkoel et al, 2000). Phenotypic abnormalities are another feature of SIOD patients and usually consist of a broad nose, lumbar lordosis, and a protruding abdomen. The SIOD disease is frequently reported to be caused by biallelic mutations in the gene SMARCAL1 (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily A-like 1), a member of the SNF2 family of proteins that regulates gene transcription, DNA replication, repair and recombination in the context of chromatin (Bansbach et al, 2010). Nonsense or frameshift mutations of SMARCAL1 can lead to a severe phenotype (Boerkoel et al, 2002), and biallelic missense mutations within the SNF2 domain in other family members were found to affect protein subcellular localization, enzymatic activity, abundances and chromatin binding, etc. (Elizondo et al, 2009)
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