A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1.

Abstract

Germline pathogenic variants in <i>DICER1</i> cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (<i>G</i>lobal developmental delay, <i>L</i>ung cysts, <i>O</i>vergrowth, <i>W</i>ilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain. Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with <i>DICER1</i> RNase III domain mutations were performed. A de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of <i>DICER1</i> was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome. The phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to <i>DICER1</i> hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome ('DICER1 syndrome plus'), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.