Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of DIS3L2

Abstract

Perlman syndrome is a rare overgrowth syndrome characterized by polyhydramnios, macrosomia, distinctive facial appearance, renal dysplasia, and a predisposition to Wilms' tumor. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. We studied a 6-year-old Japanese female patient, who was diagnosed with Perlman syndrome, with novel compound heterozygous mutations in DIS3L2 (c.[367-2A > G];[1328T > A]), who has survived long term. Most reported DIS3L2 mutations have been the homozygous deletion of exon 6 or exon 9, and these mutations would certainly have caused the loss of both RNA binding and degradation activity. We have identified new compound heterozygous mutations in the DIS3L2 of this long-term survivor of Perlman syndrome. The reason our patient has survived long-term would be a missense mutation (c.1328 T > A, p.Met443Lys) having retained RNA binding in both the cold-shock domains and the S1 domain, and through partial RNA degradation. If partial exonuclease functions remain in at least one allele, long-term survival may be possible. Further studies of Perlman syndrome patients with proven DIS3L2 mutations are needed to clarify genotype-phenotype correlation.

Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells

“…In addition to pre-let-7, it has also been reported to target histone mRNAs and many small noncoding RNAs (Labno et al 2016;Pirouz et al 2016;Reimao-Pinto et al 2016;Ustianenko et al 2016). While somatic mutations in DIS3L2 occur in sporadic Wilms tumors, germline mutations in DIS3L2 result in Perlman syndrome, an overgrowth syndrome characterized by neonatal death, genitourinary (GU) anomalies, hypotonia, neurodevelopmental delay, and frequent Wilms tumors (Astuti et al 2012;Higashimoto et al 2013;Soma et al 2017). DIS3L2 mutations in both Perlman-associated and sporadic cases of Wilms tumor suggest the importance of this gene as a tumor suppressor, yet the mechanisms through which it functions as such remain unclear.…”

Co‐occurrence of orofacial clefts and clubfoot phenotypes in a sub‐Saharan African cohort: Whole‐exome sequencing implicates multiple syndromes and genes

“…It is a common observation at Cleft‐Craniofacial Clinic at KATH that patients with multiple congenital anomalies that include OFCs have relatively low survival rate. This is probably due to the high risk of peri‐natal death that is characteristic of certain genetic syndromes, such as Perlman syndrome (Soma et al, 2017), as well as probable infanticide that is fueled by stigma together with psychosocial and socioeconomic challenges (Camille et al, 2014).…”

“…DIS3L2 also partake in several physiological and biological processes, including cell proliferation, differentiation, division, and apoptosis (Labno et al, 2016). Compound heterozygote variants in DIS3L2 cause Perlman Syndrome, an overgrowth syndrome characterized by the high neonatal mortality rate (Soma et al, 2017). Consistent with this high neonatal mortality rate, medical records at the Cleft‐Craniofacial Clinic at KATH suggest that this proband did not survive up to 3 months, after which cleft lip reconstructive surgery is normally carried out.…”

How hydrolytic exoribonucleases impact human disease: Two sides of the same story

“…2 . Germline mutations in hDIS3L2 have been associated with PRLMNS, a rare congenital overgrowth disease, with high neonatal mortality [ 51 , 70 , 71 , 72 ]. Because it has autosomal recessive inheritance, the PRLMS only manifests itself if there is a biallelic abnormality in the gene that encodes hDIS3L2.…”