DICER1 Syndrome via the DICER1 Gene

DICER1 syndrome, formerly known as pleuropulmonary blastoma (PPB) familial tumor and dysplasia syndrome, causes many different types of tumors including pleuropulmonary blastomas, cystic nephromas, ovarian Sertoli-Leydig type tumors and infrequently other tumor types. It also includes familial multinodular goiter (MNG; Foulkes et al. Human Mutation, 32(12): 1381–1384, 2011; Sabbaghian et al. J Med Genet 49:417-419, 2012). PPBs are rare pediatric lung tumors that occur before 6 years of age (Priest et al. J Pediatr 128:220-4, 1996). Cystic nephroma is a rare benign renal tumor that presents as a multicystic renal mass without solid nodules and occurs 50% of the time in children less than 4 years of age and 30% of the time in 50-70 year olds (Stamatiou et al. Cases J 1:267, 2008). Ovarian Sertoli-Leydig tumors, sex cord tumors that exhibit testicular differentiation, typically appear in affected individuals in their 20s and 30s (Young et al. Am J Surg Pathol 9:543-69, 1985).

DICER1 syndrome is caused by variants in DICER1, which encodes an RNase endonuclease that is involved in the production of microRNAs (miRNAs). miRNAs are non-protein-coding small RNAs that control post-transcriptional mRNA expression of over 30% of protein-coding genes. During transcription of miRNAs, they are required to be processed from their original long form, pri-miRNAs, to pre-miRNAs, where DICER1 processing results in a double stranded miRNA duplex, which is then unwound to form mature miRNAs. Deregulation of miRNA processing and expression has been implicated in numerous cancers. DICER1 variants can be inherited or arise de novo. DICER1 syndrome acts through an autosomal dominant mechanism, and DICER1 variants are hypothesized to result in haploinsufficiency (Slade et al. J Med Genet 48:273-278, 2011); however, DICER1 variants may exhibit incomplete penetrance as some individuals with DICER1 variants appear phenotypically normal (Hill et al. Science 325:965, 2009).

The clinical sensitivity of DICER1 variants has not been firmly established; however, Slade et al. (2011) found DICER1 variants in 79% (11/14) of PPB cases, 67% (2/3) of cystic nephroma cases, and 57% (4/7) of ovarian Sertoli- Leydig-type cases. Germline DICER1 variants in other types of tumors are rare (Slade et al. J Med Genet 48:273-278, 2011; Foulkes et al. Human Mutation, 32(12): 1381–1384, 2011). Several families have been reported to have familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors (Rio Frio et al. JAMA. Jan 5;305(1):68-77, 2011).

This test provides full coverage of all coding exons of the DICER1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.