DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis
Barbara Rivera, … , Marc R. Fabian, William D. Foulkes
Barbara Rivera, … , Marc R. Fabian, William D. Foulkes
Published December 5, 2019
Citation Information: J Clin Invest. 2020;130(3):1479-1490. https://doi.org/10.1172/JCI130206.
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Clinical Medicine Genetics Oncology

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

Abstract

BACKGROUND DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODS Whole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K–positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTS We identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSION We identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDING Canadian Institutes of Health Research, Compute Canada, Alex’s Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d’Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.

Authors

Barbara Rivera, Javad Nadaf, Somayyeh Fahiminiya, Maria Apellaniz-Ruiz, Avi Saskin, Anne-Sophie Chong, Sahil Sharma, Rabea Wagener, Timothée Revil, Vincenzo Condello, Zineb Harra, Nancy Hamel, Nelly Sabbaghian, Karl Muchantef, Christian Thomas, Leanne de Kock, Marie-Noëlle Hébert-Blouin, Angelia V. Bassenden, Hannah Rabenstein, Ozgur Mete, Ralf Paschke, Marc P. Pusztaszeri, Werner Paulus, Albert Berghuis, Jiannis Ragoussis, Yuri E. Nikiforov, Reiner Siebert, Steffen Albrecht, Robert Turcotte, Martin Hasselblatt, Marc R. Fabian, William D. Foulkes

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Figure 1

Pedigree of the family: clinical data and genotypes of a family kindred with germline DGCR8 variant c.1552G>A, p.E518K.

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Pedigree of the family: clinical data and genotypes of a family kindred ...
dx, diagnosis. Person I-1 was diagnosed with a multinodular goiter (MNG) and with a schwannoma (schw). Person II-1 was diagnosed with MNG. Person II-2 had MNG, a mature cystic teratoma, 9 schwannomas, and an ovarian serous cystadenofibroma. Individual III-1 was diagnosed with autism spectrum disorder (ASD) and MNG, and had a choroid plexus papilloma (CPP) WHO stage I and multiple schwannomas. III-3 was diagnosed with MNG and multiple schwannomas. Person III-2 was diagnosed with MNG and a single schwannoma located in the right knee. Chromatograms display the c.1552G>A;p.E518K locus in germline DNA (gDNA, blue circle) and tumor/MNG DNA (tissue DNA [tDNA], red circle) for each affected individual. Representative chromatograms show LOH in individuals I-1, II-1, II-2, III-1, III-2, and III-3. Schwannoma samples from III-2 and III-3 had a remnant of the WT allele, likely due to normal tissue contamination. The chromatograms for the MNG tDNA in III-1, III-2, and III-3 are representative of the Sanger sequencing results for all 3 nodules in each patient. All results are summarized in Supplemental Tables 3–6 and Supplemental Figures 5 and 6. Arrow indicates a WT genotype. Asterisk indicates presence of the mutant base. Three nodules of the MNG were sequenced for II-1, III-1, III-2, and III-3. Germline DNA with WT sequence at the c.1552G;p.E518 locus is shown for unaffected individual III-5. No tumor DNA from the schwannomas of III-1 and from the MNG of I-1 was available.