Mendeliome
Gene: DGCR8 Red List (low evidence)Red List (low evidence)
1 family with 6 affected individuals with early-onset MNG (6/6) and adult-onset schwannomatosis (5/6). Whole-exome sequencing identified a variant in DGCR8 gene (c.1552G>A; p.E518K) which segregated with disease.
Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumours. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumours revealed a common profile among E518K hemizygous tumours. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.Created: 2 Oct 2025, 2:46 p.m. | Last Modified: 2 Oct 2025, 2:46 p.m.
Panel Version: 1.3249
Phenotypes
Schwannoma, MONDO:0002546; Early-onset multinodular goiter and schwannomatosis, no MIM#
I don't know
PMID: 34821987 - a 35-year-old male patient reported with thyroid nodules, papillary thyroid cancer and 6 schwannomas. Harbours the suspected oncogenic E518K variant supportive of a six hit, three-step model. Note, loss-of-function of DGCR8 is not compatible with tumour disease development in this model (hence 22q11.2 deletion syndrome would not be associated with schwannomatosis/thyroid tumours).Created: 24 May 2024, 1:06 a.m. | Last Modified: 24 May 2024, 1:06 a.m.
Panel Version: 1.1796
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Early-onset multinodular goiter and schwannomatosis
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Red List (low evidence)
A germline missense variant segregates in one family with autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter (MNG) with schwannomatosis. The missense is also a recurrent somatic missense variant in Wilms tumour. (PMID:31805011)
Sources: LiteratureCreated: 24 Apr 2020, 12:12 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Early-onset multinodular goiter and schwannomatosis
Publications
Phenotypes for gene: DGCR8 were changed from Schwannoma, MONDO:0002546 to Schwannoma, MONDO:0002546; Early-onset multinodular goiter and schwannomatosis, no MIM#
Source Literature was removed from DGCR8. Source Expert list was added to DGCR8. Phenotypes for gene: DGCR8 were changed from Early-onset multinodular goiter and schwannomatosis to Schwannoma, MONDO:0002546
Gene: dgcr8 has been classified as Red List (Low Evidence).
Gene: dgcr8 has been classified as Red List (Low Evidence).
gene: DGCR8 was added gene: DGCR8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DGCR8 were set to 31805011 Phenotypes for gene: DGCR8 were set to Early-onset multinodular goiter and schwannomatosis Review for gene: DGCR8 was set to RED
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.