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Germline mutations in SMARCB1 predispose individuals to the development of rhabdoid tumors, familial schwannomatosis, and Coffin-Siris Syndrome. Coffin-Siris syndrome is characterized by cognitive impairment, fifth digit nail hypoplasia, and distinctive facial features including a wide mouth with thick everted lips, broad nasal bridge and tip, thick eyebrows, and long eyelashes. A recent publication reported mutations of SMARCB1 in four individuals presenting with clinical characteristics of Coffin-Siris syndrome.1
Molecular Genetics: The SMARCB1 gene codes for a subunit of a chromatin remodeling complex. For the past two decades, SMARCB1 has been classified as a tumor suppressor gene, with loss of function of the gene associated with predisposition to malignancy. Much more recently, the gene has been associated with cognitive impairment and multiple congenital anomalies, though it is thought that the mechanism is different. Tumors demonstrate homozygous inactivating mutations or deletions whereas heterozygous gain-of-function mutations cause syndromic cognitive impairment.1 The testing strategy is also different. For individuals with a personal history of rhabdoid tumor, or multiple schwannomas, analyzing tumor tissue first is the best course of action. Once the tumor associated mutations have been identified, the individual can be screened for those specific mutations in their blood to determine if they are somatic or germline genetic alterations. If tumor tissue is unavailable, full sequencing and deletion analysis (deletion analysis is an additional order) using DNA from a blood specimen will suffice. It’s important to note that gonadal mosaicism in an unaffected parent can result in multiple affected siblings with rhabdoid tumors,as has been previously reported.2 For individuals with clinical features of Coffin-Siris syndrome, ordering SMARCB1 sequencing on a blood specimen is the appropriate test. 1. Tsurusaki Y, Okamoto N, Ohashi H, et al. Mutations affecting components of t
Direct sequence analysis of 9 coding exons
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