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Intellectual disability

Gene: INTS1

Green List (high evidence)

INTS1 (integrator complex subunit 1)
EnsemblGeneIds (GRCh38): ENSG00000164880
EnsemblGeneIds (GRCh37): ENSG00000164880
OMIM: 611345, Gene2Phenotype
INTS1 is in 2 panels

3 reviews

Ivone Leong (Genomics England Curator)

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.

Konstantinos Varvagiannis (Other)

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

Zornitza Stark (Australian Genomics)

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571
  • Hypotonia
  • Global developmental delay
  • Cataract
  • Abnormality of the skeletal system
OMIM
611345
Clinvar variants
Variants in INTS1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

3 Oct 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

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

14 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: ints1 has been classified as Green List (High Evidence).

14 Feb 2019, Gel status: 1

Set Phenotypes

Ivone Leong (Genomics England Curator)

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

14 Feb 2019, Gel status: 1

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: INTS1 were changed from to Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system

14 Feb 2019, Gel status: 1

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: INTS1 were set to 28542170

28 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to INTS1.

22 Jun 2018, Gel status: 0

Added New Source

Zornitza Stark (Australian Genomics)

INTS1 was added to Intellectual disability panel. Sources: Literature

22 Jun 2018, Gel status: 0

Created

Zornitza Stark (Australian Genomics)

INTS1 was created by Zornitza Stark