DICER1 – Global Developmental Delay–Lung Cysts–Overgrowth–Wilms Tumour (GLOW) Syndrome

DICER1 encodes an RNase III endoribonuclease critical for microRNA biogenesis. Germline or mosaic missense mutations in the RNase III domains of DICER1 cause a distinct phenotype termed GLOW syndrome, defined by global developmental delay, lung cysts, overgrowth and Wilms tumour.

Three unrelated probands demonstrated de novo or mosaic RNase III domain variants: one heterozygous c.4031C>T (p.Ser1344Leu) affecting the RNase IIIa domain ([PMID:33208384]) and two hotspot mosaic variants c.5126A>G (p.Asp1709Gly) and c.5125G>T (p.Asp1709Tyr) in the RNase IIIb domain ([PMID:24676357]). These variants occurred in the absence of additional pathogenic alleles and no familial segregation was observed, consistent with an autosomal dominant mechanism with mosaicism.

Inheritance is autosomal dominant, typically arising as de novo or mosaic missense changes in critical metal‐binding residues of the RNase III domains. No affected relatives have been reported (affected_relatives=0).

Functional studies reveal that RNase IIIa–Ser1344 and RNase IIIb metal‐binding site mutations impair 5p miRNA biogenesis while preserving 3p strand production, analogous to established DICER1 hotspot mutations. Murine cell models and patient tumour analyses confirm neomorphic/hypomorphic activity and disrupted miRNA processing concordant with the human phenotype ([PMID:33208384]; [PMID:24676357]).

No reports to date dispute this association.

Collectively, genetic and experimental data support a ClinGen Moderate gene–disease association for DICER1 in GLOW syndrome. Identification of pathogenic RNase III domain variants enables molecular diagnosis and informs surveillance for Wilms tumour in affected children.

References

• Journal of medical genetics • 2022 • A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1. PMID:33208384
• Journal of medical genetics • 2014 • Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome. PMID:24676357

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