Intellectual disability - microarray and sequencing
Gene: INTS1 Green List (high evidence)Comment on list classification: Promoted from red to green based on the new evidence provided by Konstantinos Varvagiannis, which shows that there are enough cases to support gene-disease association.Created: 14 Feb 2019, 1:37 p.m.
Green List (high evidence)
Oegema et al. (2017 - PMID: 28542170) reported 3 unrelated individuals with moderate to severe cognitive delay (3/3), cataracts (3/3) as well some additional common skeletal/facial features. All subjects, were of Dutch ancestry and harbored a nonsense INTS1 variant in the homozygous state [NM_001080453.2:c.5351C>A or p.(Ser1784*)]. A region of homozygosity shared by all 3, suggested that the mutation originated from a common ancestor. qRT-PCR in patient fibroblasts demonstrated significantly reduced mRNA levels compared to controls.
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Krall et al. (2019 - PMID: 30622326) report on 5 additional individuals (2 pairs of sibs and an additional subject) with biallelic INTS1 variants. The authors provide some further clinical information on the 3 subjects previously reported by Oegema et al.
One sib pair was found to harbor a missense variant (p.Arg77Cys) as well as frameshift one (p.Arg1800Profs*20) in the compound heterozygous state. Sibs in the second family were homozygous for a further missense variant (p.Pro1874Leu). The fifth individual harbored a frameshift variant (p.Leu1764Cysfs*16) in trans with a missense one (p.Leu2164Pro).
As p.Arg77Cys has been seen in the homozygous state in one subject in gnomAD, the authors comment that pathogenicity of this variant is unclear. They further suggest that this may be a hypomorphic variant. Incomplete penetrance or development of manifestations when this variant is in trans with a more severe one, are among the hypotheses discussed.
All 5 individuals as well as the 3 previously reported ones, demonstrated a highly overlapping phenotype consisting of hypotonia (8/8), cognitive delays (8/8), cataracts (8/8) with - in some cases - additional ophthalmologic findings as well as some common facial/other features.
INTS1 encodes the integrator complex subunit 1 (the complex comprises 14 subunits).
Homozygous Ints1 mutation in mice results in embryonic lethality at the blastocyst stage [PMID cited: 17544522 - http://www.informatics.jax.org/marker/MGI:1915760].
In zebrafish ints1 is expressed in the developing eye. By targeting of ints1 using CRISPR/Cas9, the authors produced zebrafish with biallelic LoF variants. Mutant larvae show abnormal lens morphology supporting involvement of INTS1 in eye and lens development.
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INTS1 is not associated with any phenotype in OMIM, nor in G2P.
This gene is included in gene panels for intellectual disability offered some by diagnostic laboratories.
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As a result, INTS1 could be considered for inclusion in the ID panel as green (or amber).Created: 28 Jan 2019, 6:33 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Publications
Variants in this GENE are reported as part of current diagnostic practice
I don't know
Three unrelated individuals with bi-allelic variants described in the literature, but ?founder effect. Consider including as Amber.Created: 22 Jun 2018, 11:24 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: INTS1 were changed from Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571
Publications for gene: INTS1 were set to 28542170; 30622326; 17544522
Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Gene: ints1 has been classified as Green List (High Evidence).
Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Phenotypes for gene: INTS1 were changed from to Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Publications for gene: INTS1 were set to 28542170
Source Victorian Clinical Genetics Services was added to INTS1.
INTS1 was added to Intellectual disability panel. Sources: Literature
INTS1 was created by Zornitza Stark
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.