DIS3L2 – Perlman syndrome

Perlman syndrome is a rare autosomal recessive overgrowth disorder characterized by prenatal overgrowth, distinctive facial features, renal dysplasia, and a high risk of Wilms tumor. Biallelic mutations in the exoribonuclease gene DIS3L2 underlie this phenotype in individuals with Perlman syndrome, consistent with autosomal recessive inheritance.

Initial mapping of a susceptibility locus to 2q37.1 and identification of germline DIS3L2 mutations in multiple families established the gene–disease link in 2012 (PMID:22306653). Subsequent reports described a homozygous exon 9 deletion due to LINE-1 mediated NAHR in a Japanese patient (PMID:23486540) and a spectrum of loss-of-function and splice-site variants across unrelated probands. Compound heterozygous missense and splice variants, including c.1328A>G (p.Met443Lys), were associated with long‐term survival, implying partial retention of exonuclease function (PMID:28328139). A recent sibship study identified compound heterozygous variants c.127C>T (p.Arg43Ter) and c.2381G>A (p.Arg794His) segregating in three affected siblings, confirming familial transmission (PMID:40704758).

Genetic evidence comprises at least 13 probands from over seven unrelated families, with segregation in two additional affected sibs (PMID:40704758) and a predominance of LoF alleles (frameshift, nonsense, splice-site) alongside hypomorphic missense changes. A recurrent exon 9 deletion hotspot suggests NAHR-driven rearrangements contribute to the variant spectrum. Although population‐level carrier frequencies are not established, the rarity of reported cases underscores low prevalence.

Functional studies demonstrate that DIS3L2 mediates decay of uridylated noncoding RNAs via the Dis3l2-mediated decay (DMD) pathway. Mouse embryonic stem cells lacking Dis3l2 accumulate oligouridylated Rmrp and other Pol III transcripts, and in vitro reconstitution confirms TUTase-Dis3l2 sufficiency for decay, aligning with human disease mechanisms (PMID:27498873).

No studies have refuted the association; the consistency of AR inheritance, segregation data, and mechanistic assays supports a definitive gene–disease relationship. Somatic DIS3L2 hits in Wilms tumor further emphasize a two-hit tumorigenesis model in affected individuals.

In summary, biallelic DIS3L2 loss-of-function or hypomorphic variants cause Perlman syndrome through disrupted RNA decay, with robust genetic segregation and concordant functional data. Genetic testing of DIS3L2 should be considered in overgrowth syndromes with renal anomalies to inform diagnosis, surveillance for Wilms tumor, and family counselling.

Key take-home: DIS3L2 testing has clear diagnostic and prognostic utility in suspected Perlman syndrome.

References

• Nature Genetics • 2012 • Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility PMID:22306653
• European Journal of Human Genetics • 2013 • Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome PMID:23486540
• American Journal of Medical Genetics Part A • 2017 • Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of DIS3L2 PMID:28328139
• Molecular Genetics & Genomic Medicine • 2025 • Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review PMID:40704758
• Cell Reports • 2016 • Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs PMID:27498873

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