Intellectual disability - microarray and sequencing
Gene: SMARCD1 Green List (high evidence)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
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
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
Red List (low evidence)
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
Red List (low evidence)
Phenotypes for gene: SMARCD1 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot; Coffin-Siris syndrome 11, 618779
Gene: smarcd1 has been classified as Green List (High Evidence).
Mode of inheritance for gene: SMARCD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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
Publications for gene: SMARCD1 were set to 26350204
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.
Publications for gene SMARCD1 was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
SMARCD1 was created by ellenmcdonagh
SMARCD1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
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.