DIS3-like 3'-5' exoribonuclease 2 (DIS3L2), an exoribonuclease, is known to preferentially degrade uridylated RNA substrates, miRNAs, and ncRNAs. Recent reports show that DIS3L2 also plays a key role in cell proliferation and tumor growth. Mutations in DIS3L2 are associated with congenital overgrowth disorders such as Perlman syndrome, yet the developmental functions of DIS3L2 remain unknown. We report the developmental role of dis3l2 in neural crest specification, patterning, and survival in the zebrafish embryo. The dis3l2 morphants exhibited reduced expression of neural crest specifier genes coupled with extensive apoptosis in the neural tissue. Our study demonstrates that dis3l2 regulates neural tissue apoptosis and progenitor functions through the Akt-GSK3β signaling pathway. Additionally, we show that dis3l2 is essential for early mitoses in the zebrafish blastula and plays a key role in maintaining spindle length at metaphase, chromosome congression, spindle pole integrity, and cytokinesis. In summary, we identify new functions of exoribonuclease dis3l2 in cell fate specification, neural crest survival, and mitosis during embryogenesis, which form the underlying basis of DIS3L2-associated Perlman syndrome. DIS3 like 3’-5’ exoribonuclease 2 (DIS3L2) degrades mRNAs and various RNA substrates in the eukaryotic cells. DIS3L2 mutations are associated with congenital overgrowth syndromes like Perlman syndrome and Wilm’s tumor. The role of DIS3L2 in regulating the embryonic processes remains poorly understood. Our study delineates the developmental functions of dis3l2 in cell fate determination, survival, and proliferation during vertebrate embryogenesis using zebrafish embryos as a model. We show that dis3l2 plays a key role in neural crest survival and patterning by modulating Akt-GSKβ signaling. We also report unique molecular functions of dis3l2 in mitotic fidelity and cytokinesis during embryonic mitoses. Our study provides novel insights into the molecular functions of dis3l2 in regulating neural tissue apoptosis during embryonic brain morphogenesis and associated CNS disorders.

Perlman syndrome is a rare autosomal recessive overgrowth disorder with a predisposition to Wilms tumor, caused by biallelic variants in DIS3L2. The majority of patients die in infancy due to respiratory and/or renal failure, limiting the reports of patients surviving into childhood. Exome sequencing was performed in the proband and her older brother. A younger sibling subsequently underwent targeted variant analysis. RNA sequencing was utilized to investigate the functional impact of the missense variant. Three siblings presented at birth with fetal macrosomia, dysmorphic facial features, and facial hypotonia. The proband had early speech delay and was diagnosed with Wilms tumor at 3 years old. Her brothers both had developmental delay presenting within the first year of life. Genetic testing identified compound heterozygous variants in DIS3L2 (NM_152383.5): c.127C>T (p.Arg43Ter) (paternal)/c.2381G>A (p.Arg794His) (maternal). Our findings expand the genetic and clinical spectrums associated with Perlman syndrome and increase the understanding of the phenotype observed in childhood. They also support consideration of genetic testing for Perlman syndrome in individuals and sibships with macrosomia, developmental delay, and characteristic facial dysmorphisms, with or without the presence of Wilms tumor.

The deletion of the DIS3L2 gene causes the extremely uncommon congenital overgrowth syndrome, known as Perlman syndrome, which is autosomal recessive. Polyhydramnios, macrosomia, facial dysmorphism, renal dysplasia, and several congenital abnormalities with Wilms tumor propensity are its defining features. Beckwith-Wiedemann syndrome (BWS), prune belly syndrome (PBS), and Simpson-Golabi-Behmel syndrome (SGBS1) have certain similar clinical characteristics with Perlman syndrome. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. Here, we present a case with the classic clinical features of Perlman syndrome and a DIS3L2 gene deletion that was discovered prenatally.

Biallelic variants in DI3SL2 cause Perlman Syndrome, associated increased risk for Wilms tumor. Cutis Marmorata Telangiectatica Congenita (CMTC) is a rare congenital disorder characterized by cutaneous vascular anomalies. We report a 2-year-old boy with both Wilms tumor and CMTC. Genetic testing, prompted by his complex presentation, revealed 1 somatic mutation and 1 familial germline mutation in the DIS3L2 gene, suggesting a 2-hit causation of Wilms tumor. Separately, a single GNA11 somatic mutation was identified to explain the CMTC. We suggest that genetic testing for germline mutations associated with Wilms tumor susceptibility be considered even in cases without known family history.

To analyze the clinical phenotype and genetic characteristics of a child with Perlman syndrome. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Whole exome sequencing (WES) was carried out to detect potential variant in the proband. Candidate variant was verified by Sanger sequencing. The pathogenicity of candidate variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). The results of WES showed that the proband has harbored compound heterozygous variants of the DIS3L2 gene, namely c.2109delC and c.1829.c.1830insC, which were respectively inherited from her mother and father. The results were confirmed by Sanger sequencing. Based on the ACMG guidelines, the two novel variants were both predicted to be pathogenic (PVS1+PS2+PM2). The compound heterozygous variants of the DIS3L2 gene probably underlay the Perlman syndrome in this patient. Above finding has enriched the spectrum of DIS3L2 gene mutations.