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Intellectual disability

Gene: MSL3

Green List (high evidence)

MSL3 (MSL complex subunit 3)
EnsemblGeneIds (GRCh38): ENSG00000005302
EnsemblGeneIds (GRCh37): ENSG00000005302
OMIM: 300609, Gene2Phenotype
MSL3 is in 3 panels

7 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: Promoted from amber to green based on the new evidence provided by Konstantinos Varvagiannis, which shows that there are enough cases to support gene-disease association. MSL3 is not associated with any phenotypes in OMIM; however, it has been confirmed to be associated with a phenotype in Gene2Phenotype with intellectual disability listed as one of the phenotypes.
Created: 25 Feb 2019, 2:03 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID 30224647 is a collaborative study on the phenotype of MSL3 pathogenic variants.

The variants included 11 truncating mutations, 1 missense SNV, 1 intragenic deletion (deletion of 1 exon), 2 larger deletions (also spanning proximal genes) as well as a chromosomal inversion. The authors propose haploinsufficiency (rather than a dominant negative effect) as the underlying mechanism.

A total of 16 individuals from 15 unrelated families are described in the study. Common features included hypotonia, feeding difficulties in early infancy, speech and motor delay as well as intellectual disability. Patients with SNVs displayed progressive spasticity or ataxic gait. The authors suggest the presence of overlapping facial features namely telecanthus, epicanthal folds, down-slant of palpebral fissures, downturned corners of the mouth as well as abnormal ears.

Although MSL3 is located on Xp22.2, hemizygous males and heterozygous females present with a comparable phenotype (6 of the 16 individuals in the study were females). In one case the chromosomal inversion was inherited from a mildly affected mother, in whom the aberration occurred as a de novo event. A pair of monozygotic twins demonstrated the same nonsense variant, not found after deep sequencing of parental leucocyte DNA suggesting of parental mosaicism. The variants in all other individuals occured as de novo events.

The study is supported by functional studies demonstrating reduction of H4K16 acetylation in patient fibroblasts compared to controls. In addition, RNA-Seq experiments were suggestive of misregulation of different developmental pathways in line with MSL3 being part of a chromatin modifying complex important for transcription regulation.

As a result this gene can be upgraded to green.
Created: 9 Oct 2018, 1:58 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Please note multiple variants submitted as likely pathogenic by clinical labs in ClinVar
Created: 19 Jun 2018, 3:18 p.m.

Publications

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

I don't know

Comment on list classification: Changed from Red to Amber, not enough evidence to confirm ID disease association to make Green from just likely pathogenic variants in ClinVar, but MSL3 is a diagnostic gene on the Intellectual disability Victorian Clinical Genetics Services panel, so changed rating to Amber and added watchlist tag.
Created: 30 Jul 2018, 4:39 p.m.
clinvar variants are not confirmed pathogenic variants but are likely pathogenic.
Created: 30 Jul 2018, 4:36 p.m.
Comment on publications: Added publication recommended by external expert review to support gene-disease association, Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders (2017) PMID: 28135719
Created: 30 Jul 2018, 4:21 p.m.
Comment on publications: Candidate intellectual disability gene suggested by Tarpey et el., (2009) and PMID:19377476 and Grozeva et al, (2015) PMID: 26350204
Created: 1 Mar 2018, 6:05 p.m.
This is a candidate intellectual disability gene Grozeva et al., (2015) PMID: 26350204, Najmabadi et al., (2011) PMID:19377476 however no evidence to date has been found to support the association between variants of this gene and an observed intellectual disability phenotype, variant only found once, nonrecurrent change. This gene is currently a confirmed DD gene in Gene2Phenotype for MSL3 syndrome.
Created: 1 Mar 2018, 6:02 p.m.

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : NA
Created: 27 Jul 2017, 7:38 p.m.

Mode of inheritance
Unknown

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Muscular hypotonia
  • Feeding difficulties
  • Neurodevelopmental delay
  • Intellectual disability
  • no OMIM number
Tags
watchlist
OMIM
300609
Clinvar variants
Variants in MSL3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: msl3 has been classified as Green List (High Evidence).

19 Feb 2019, Gel status: 2

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: MSL3 were changed from to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number

19 Feb 2019, Gel status: 2

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MSL3 were set to 26350204; 19377476; 28135719; 25529582

29 Sep 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to MSL3.

30 Jul 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: msl3 has been classified as Amber List (Moderate Evidence).

30 Jul 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: MSL3 were set to 26350204; 19377476; 28135719; 25529582

30 Jul 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: MSL3 were set to 26350204; 19377476; 28135719

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

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.

12 Mar 2018, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene MSL3 was set to ['26350204', '19377476']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

MSL3 was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

MSL3 was created by ellenmcdonagh