PT - JOURNAL ARTICLE AU - Emeli Pontén AU - Sofia Frisk AU - Fulya Taylan AU - Raquel Vaz AU - Sandra Wessman AU - Leanne de Kock AU - Niklas Pal AU - William D Foulkes AU - Kristina Lagerstedt-Robinson AU - Ann Nordgren TI - A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1 AID - 10.1136/jmedgenet-2020-107385 DP - 2022 Feb 01 TA - Journal of Medical Genetics PG - 141--146 VI - 59 IP - 2 4099 - http://jmg.bmj.com/content/59/2/141.short 4100 - http://jmg.bmj.com/content/59/2/141.full SO - J Med Genet2022 Feb 01; 59 AB - Background Germline pathogenic variants in DICER1 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 (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.Methods Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed.Results A de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.Conclusion 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 DICER1 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.