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Intellectual disability

Gene: SMARCD1

Green List (high evidence)

SMARCD1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 1)
EnsemblGeneIds (GRCh38): ENSG00000066117
EnsemblGeneIds (GRCh37): ENSG00000066117
OMIM: 601735, Gene2Phenotype
SMARCD1 is in 2 panels

6 reviews

Cristina Dias (The Francis Crick Institute)

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
developmental delay; intellectual disability; hypotonia; feeding difficulties; small hands; small feet

Publications

Ivone Leong (Genomics England Curator)

Comment on list classification: Promoted from red to green. SMARCD1 is not associated with any phenotype in OMIM or Gene2Phenotype. After consulting with the Genomics England Clinical Team and based on the submitted expert review, it was decided that there is enough evidence to promote this gene to green status.
Created: 9 Jul 2019, 3:37 p.m. | Last Modified: 9 Jul 2019, 3:37 p.m.
Panel Version: 2.944

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Nixon et al. (2019 - https://doi.org/10.1016/j.ajhg.2019.02.001) report on 5 unrelated individuals with SMARCD1 mutations. Features included among others hypotonia (3/5), feeding difficulties (5/5), DD (5/5) and ID (4/5 - one further subject was too young for evaluation) and anomalies of the hands/feet (and 5th digit in some).

SMARCD1 encodes a component of the SWI/SNF chromatin remodeling complex. Mutations in 11 (of 28) genes encoding SWI/SNF components are involved in syndromic or non-syndromic neurodevelopmental disorders (eg. Nicolaides-Baraitser syndrome, Coffin-Siris syndrome, etc) with which the SMARCD1-related phenotype showed some degree of overlap (eg. DD/ID, anomalies of the 5th digit - with the exception of facial features).

Most variants (4/5) had occurred as de novo events while for one individual parental sample was unavailable. 2 nonsense [NM_003076.4:c.1457G>A or (p.Trp486*) and c.1507C>T (p.Arg503*)] and 3 missense SNVs [c.990C>G (p.Asp330Glu) / c.1336A>G (p.Arg446Gly) / c.1483T>C (p.Phe495Leu)] are reported.

The variants identified cluster in the C-terminal end of the protein. Missense variants were proximaly located in a 3D model of the protein. The 2 nonsense variants were predicted to escape NMD and upon immunoblot, amounts of Asp330Glu, Trp486*, Phe495Leu mutant protein were similar to wt. The 3 variants did not impair the binding/interaction of SMARCD1 to SMARCA4 and SMARCC1 and its incorporation into the SWI/SNF complex.

SMARCD1 appears to be intolerant to LoF variants (pLI of 1 in ExAC). It is equally releatively intolerant to missense variants (Z-score of 3.95). The %HI index for haploinsufficiency is 16.64% (close to the high ranking genes). As the authors note, the precise functional effect of the 5 mutations is not however known.

Targeted knockdown of the Drosophila ortholog Bap60 in the mushroom body of adult flies, led to defects in long-term memory. Transcriptome analysis revealed downregulation of neuron-related genes in the mushroom body of early juvenile adult Bap60-knockdown flies (0-3 hours after eclosion). This period is considered to be critical for the establishment of of synaptic connections required for learning and memory.

SMARCD1 is not commonly included in gene panels for ID offered by diagnostic laboratories. The gene is not associated with any phenotype in OMIM, nor in G2P.

As a result, SMARCD1 can be considered for upgrade to green (or amber) in the current panel.
Created: 16 Mar 2019, 7:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot

Publications

  • https://doi.org/10.1016/j.ajhg.2019.02.001

Caroline Wright (Sanger)

Red List (low evidence)

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

The Green review by Cristina Dias supports the current Green rating of SMARCD1.
Created: 20 Sep 2019, 8:57 p.m. | Last Modified: 20 Sep 2019, 8:57 p.m.
Panel Version: 2.1039
Candidate ID gene in PMID:26350204 but no strong evidence to support ID causation.
Created: 31 Oct 2017, 9:24 a.m.

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Generalized hypotonia
  • Feeding difficulties
  • Global developmental delay
  • Intellectual disability
  • Abnormality of the hand
  • Abnormality of the foot
OMIM
601735
Clinvar variants
Variants in SMARCD1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

9 Jul 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: smarcd1 has been classified as Green List (High Evidence).

9 Jul 2019, Gel status: 1

Set mode of inheritance

Ivone Leong (Genomics England Curator)

Mode of inheritance for gene: SMARCD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

9 Jul 2019, Gel status: 1

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: SMARCD1 were changed from to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot

1 Jul 2019, Gel status: 1

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: SMARCD1 were set to 26350204

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.

29 Nov 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene SMARCD1 was set to ['26350204']

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)

SMARCD1 was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

SMARCD1 was created by ellenmcdonagh