Intellectual disability - microarray and sequencing
Gene: MIR17HG Amber List (moderate evidence)Comment when marking as ready: All cases to date have been CNVs. Need further evidence as to critical region / whether SNVs present in similar manner.Created: 8 Mar 2018, 2:35 p.m.
Comment on list classification: Sufficient cases associated with copy number losses, however no reported cases to date of SNVs with this phenotype (includes personal correspondence with colleagues undertaking diagnostic testing). The smallest deletion reported encompasses the gene but also includes the first exon of the neighbouring gene, GPC5. Await SNV cases or deletions only including this gene to prompt review.Created: 8 Mar 2018, 2:34 p.m.
Comment on list classification: Promoted gene status from Red to Green, although rare and the phenotype has been extended Feingold syndrome 2, it has been described in six patients worldwide (Sirchia et a.,l (2017) PMID: 28159702. All cases have been described with a form of ID. However no SNV cases in the literature, so needs internal clinical review for confirmation of rating.Created: 6 Mar 2018, 5:25 p.m.
Comment on publications: Recent papers have gone on to expand the phenotypes of Feingold syndrome-2, illustrating the phenotypic variability within the clinical presentation of Feingold syndrome-2 and highlights considerable overlap with Feingold syndrome-1 but they have all to date included some intellectual disability.
Grote LE et al,. (2015) PMID: 26360630 described a patient that had characteristic digital anomalies and short stature often seen in Feingold syndrome-2 with mild learning difficulties but with with less common features of a congenital heart defect and hearing loss. Additionally, the patient did not have microcephaly.
Sirchia F et al,. (2017) PMID: 28159702 reported a novel phenotypic association of Feingold syndrome type 2 and keratoconus, a likely contiguous gene syndrome due to a large genomic deletion on 13q spanning MIR17HG and a still to be identified gene for keratoconus.Created: 6 Mar 2018, 5:20 p.m.
Comment on publications: Fiori E, Babicola et al., (2015) PMID: 26026879. Mouse model for Feingold syndrome 2.Created: 6 Mar 2018, 4:54 p.m.
Comment on publications: Fourth case was described Ganjavi H et al., (2014) PMID: 25391829 in an 18-year-old girl with microcephaly, short stature, mildly dysmorphic features, digital malformations and significant cognitive and psychiatric symptoms. Comparative genomic hybridisation array testing confirmed a 7.4 Mb microdeletion in chromosome region 13q31.1q.31.3 corresponding to the MIR17HG gene.Created: 6 Mar 2018, 4:44 p.m.
Comment on publications: De Pontual et al. (2011) PMID:21892160 identified three probands with Feingold syndrome type 2. Two female probands were identified via high-resolution CGH arrays identifying germline hemizygous microdeletions at chromosome 13q31.3 that segregated with disease in both families
In additon to this De Pontual et al. (2011) then searched
the DECIPHER database (Firth et al., 2009 PMID:19344873) and they identified a third proband who had a 180-kb hemizygous 13q31.3 microdeletion encompassing the entire MIR17HG gene and the first exon of GPC5. The third patient was not classified as having Feingold syndrome, but displayed a combination of features compatible with the diagnosis.Created: 6 Mar 2018, 1:57 p.m.
Comment on phenotypes: Added phenotype from OMIM and Orphanet. Feingold syndrome type 2 (FS2) is a rare inherited malformation syndrome characterized by skeletal abnormalities and mild intellectual disabilities similar to those seen in Feingold syndrome type 1 (FS1; see this term) but that lacks the manifestations of gastrointestinal atresia and short palpebral fissures.Created: 6 Mar 2018, 10:35 a.m.
added tag locus-type-rna-long-non-coding, deletions and watchlist tagCreated: 6 Mar 2018, 10:28 a.m.
I don't know
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
FEINGOLD SYNDROME
Publications
Added tag to explain why there is no Ensembl gene ID for this entity.Created: 6 Jan 2017, 3:44 p.m.
I don't know
Comment on list classification: Three families with deletions of MIR17HG reported. Requires further data before diagnostic gradeCreated: 7 Feb 2016, 11:24 p.m.
Source: Expert Review Red was removed from gene: MIR17HG
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Expert Review Amber was added to MIR17HG. Panel: Intellectual disability Model of inheritance for gene MIR17HG was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene MIR17HG was set to ['21892160', '19344873', '25391829', '26360630']
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Red List (Low Evidence).
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
MIR17HG was created by ellenmcdonagh
MIR17HG was added to Intellectual disabilitypanel. Sources: Expert Review Amber
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 [email protected]
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.