Identification of two 14q32 deletions involving DICER1 associated with the development of DICER1-related tumors
Introduction
DICER1 encodes an RNase III endonuclease protein that regulates the production of small non-coding RNAs. These non-coding RNAs function to repress gene expression in a variety of cellular processes during development and when misregulated, can be associated with cancer development (Bartel, 2004; Foulkes et al., 2014). Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome (DICER1 syndrome) which confers an increased risk for development of a wide range of rare childhood and adult-onset tumors, the most common of which include pleuropulmonary blastoma (PPB), ovarian sex cord-stromal tumors (particularly Sertoli–Leydig cell tumor (SLCT)), cystic nephroma (CN), and multinodular goiter (MNG) (Doros et al., 2014; Foulkes et al., 2014). Other less frequent tumor types include Wilms’ tumor (WT), differentiated thyroid carcinoma (DTC), pineoblastoma, and pituitary blastoma. The development of tumors in DICER1 syndrome has been reported to act through a two-hit model, with a primary (germline) loss-of-function type mutation and a secondary (somatic) mutation, which typically occurs within the DICER1 RNase IIIb domain (Doros et al., 2014; Foulkes et al., 2014). Penetrance, or risk for tumor development in DICER1 syndrome, is unknown, but has been estimated to be 15% or less, with a higher incidence observed in females (Foulkes et al., 2014).
The spectrum of germline DICER1-syndrome-associated mutations shows a high prevalence and broad distribution of heterozygous sequence-level alterations, including missense, nonsense, and splice-site mutations, as well as small deletions and insertions (Hill et al., 2009; Doros et al., 2014; Foulkes et al., 2014). Although there are well over 100 reported DICER1 sequence-level variants associated with tumor development, thus far few patients with DICER1 whole gene deletions have been reported in the literature, and only two recently reported cases have been identified in association with DICER1-related tumor development (Zollino et al., 2009; Piccione et al., 2010; Zampini et al., 2012; Foulkes et al., 2014; Ting et al., 2016; van Engelen et al., 2017; de Kock et al., 2018). Here we present the clinical findings of three additional patients, from two unrelated families, with 14q32 deletions encompassing the DICER1 locus, one of which is the smallest reported to date. Two of these patients have a history of DICER1-related tumors, which provides additional insight into the tumor risks associated with DICER1 whole gene deletions. These findings also expand upon the clinical significance of deletions within 14q32.
Section snippets
Clinical description
A pedigree summarizing the clinical findings and test results for Family I is presented in Fig. 1. The proband (individual IV-1) was a 6-year-old male referred for genetic evaluation due to a history of impulsive behaviors and global developmental delays, including speech delay and fine and gross motor delays. Clinical findings included mild hypotonia, macrocephaly (OFC 56 cm, >99 %ile), obesity (43.727 kg, >99%ile), and tall stature (129.5 cm, >99 %ile). Physical examination revealed no
Methods
Constitutional genetic testing by CMA and FISH was performed for Family I at ARUP Laboratories (Salt Lake City, UT, U.S.A.) using either peripheral blood (for the proband (IV-1) and his mother (III-5)) or buccal tissue (for the maternal grandfather (II-1) and maternal half sibling (IV-2)). CMA was performed using the CytoScan® HD platform and analyzed using Chromosome Analysis Suite software (Affymetrix, Santa Clara, CA, U.S.A.). A custom metaphase FISH analysis was performed on the proband and
Discussion
To date, over 130 germline sequence-level variants have been identified in association with DICER1-syndrome, the vast majority of which are predicted and/or supported by functional assays to result in a loss-of-function. These mutations are associated with a predisposition for the development of multiple childhood and adult onset tumors (Foulkes et al., 2014). However, due to the scarcity of reported DICER1 whole gene deletions, it is difficult to counsel patients on whether DICER1 deletions
Acknowledgments
We sincerely thank the patients and their families for their participation in this study. We also thank Erin Riggs (Coordinator, ClinGen) for facilitating this collaboration through ClinGen/ClinVar. Support for this research was provided by the ARUP Institute for Clinical and Experimental Pathology.
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