FAM6A; PRLMNS; hDIS3L2
The DIS3L2 gene is associated with autosomal recessive Perlman syndrome (MedGen UID: 162909). Additionally, the DIS3L2 gene has preliminary evidence supporting a correlation with autosomal dominant non-syndromic Wilms tumor (PMID: 25670083).
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Invitae tests that include this gene:
DIS3L2 gene encodes a nuclear ribonuclease that is part of the exosome complex involved in RNA metabolism and control of cell growth and division.
MedGen UID: 162909
The DIS3L2 gene is associated with autosomal recessive Perlman syndrome.
Perlman syndrome is an overgrowth disorder characterized by polyhydramnios, fetal ascites, fetal/neonatal macrosomia, hypotonia, organomegaly, renal dysplasia, nephroblastomatosis, and high risk of Wilms tumor (PMID: 23613427).
Additional findings include diaphragmatic hernia, volvulus, distal ileal atresia, hypertrophy of the islets of Langerhans, hyperinsulinism, interrupted aortic arch, cryptorchidism, characteristic facial features (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, micrognathia, upsweep of anterior scalp hair, low-set ears), corpus callosum agenesis, cerebral atrophy, grey matter heterotopias, white matter hypoplasia, and developmental delay (PMID: 22306653, 18780370).
The incidence of Wilms tumor in those who survive the neonatal period has been estimated at 64% (PMID: 18780370). The tumor is diagnosed at an earlier age compared with sporadic cases (less than 2 years versus 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%) (PMID: 22306653). Histologic examination of the kidneys in individuals with Perlman syndrome frequently shows nephroblastomatosis, which is a precursor lesion for Wilms tumor (PMID: 22306653).
The DIS3L2 gene has high sequence similarity with catalytic exosome subunits that function as 3’-5’-exoribonucleases. 3’-5’-exoribonucleases mediate the degradation of mRNAs that have been polyuridylated at the 3’ end. The transcript is essential for ensuring correct mitosis, regulation of cell proliferation, and is believed to play a role in the maintenance of embryonic stem cells ( UniProtKB – Q8IYB7 (DI3L2_HUMAN). Accessed April 2016).
Perlman syndrome is an autosomal recessive condition that results when an individual inherits a pathogenic DIS3L2 variant from each parent. For there to be a risk of Perlman syndrome in offspring, both the patient and their partner would each have to carry a pathogenic variant in DIS3L2. In this case, the risk of having have an affected child is 25%.
It is suggested that management for Perlman syndrome be supportive and multidisciplinary ( Orphanet: ORPHA2849. Perlman syndrome. Accessed April 2016). Lapunzina has proposed the following medical management protocol (PMID: 16010678):
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.
Knowing if a pathogenic variant is present in the DIS3L2 gene is advantageous. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant DIS3L2 information is likely to become available in the near future. Awareness of this variant encourages patients and their providers to inform at-risk family members, to consider implementing established screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Review date: July 2016
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|