Intellectual disability - microarray and sequencing
Gene: SPART Green List (high evidence)Comment when marking as ready: Although primarily a HSP presentation, Table 1 in PMID 20437587 summarises the clinical features in cases to date. There is delayed language acquisition and motor skills, almost universally, alongside poor school performance and therefore on balance, it should be included. However, I accept that the diagnostic confidence in the absence of spasticity will be limited.Created: 14 Nov 2017, 9:42 a.m.
Green List (high evidence)
Rated Green based on >3 unrelated cases of SPG20 homozygous variants causing Troyer syndrome (MIM:275900), which includes developmental delay. PMID:28679690 presents a recent (2017) case and summary. Biallelic MOI supported by OMIM.Created: 29 Nov 2017, 11:19 a.m.
Dardour et al. (2017, PMID:28679690) report 3 brothers of a conanguineous Moroccan family with severe ID and a homozygous c.1369C>T (p.Arg457*) variant in SPG20.Created: 19 Sep 2017, 2:30 p.m.
Tawamie et al. (2015, PMID:26003402) reported 2 sibs, born of consanguineous Turkish parents, with complicated spastic paraplegia. The patients were 26 and 17 years of age at the time of the report. The older sister had delayed psychomotor development in infancy. Her IQ was 46. Her brother had developmental delay. They identified the c.364delAT in exon 2 of SPG20, and haplotype analysis confirmed that the variant occurred independently of the same variation reported by Manzini.Created: 19 Sep 2017, 2:30 p.m.
Manzini et al. (2010, PMID:20437587) reported a large Omani kindred with SPG20. All affected individuals presented with short stature and dysarthria, and showed delayed motor and cognitive development. A 2bp deletion (c.364_365delAT) was identified in the first coding exon of SPG20, resulting in a frameshift and premature termination. Unaffected indivs were heterozygous.Created: 19 Sep 2017, 2:29 p.m.
Bakowska et al. (2008, PMID:18413476) reported an Amish brother and sister from Ohio with Troyer syndrome (MIM:275900). Both showed delayed motor and cognitive development and developed a progressive deterioration in gait and speech during childhood. The SPG20 1110delA mutation was present in both siblings.Created: 19 Sep 2017, 2:28 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Troyer syndrome (MIM:275900); developmental delay
Publications
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_movement_disorder_list . Main mutation mechanism : NACreated: 27 Jul 2017, 8:33 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : manju_list; neuro_20160418_strict; NA. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation TrustCreated: 19 Jul 2017, 1:26 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Comment on phenotypes: fixed formatCreated: 19 Dec 2017, 5:01 p.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to assess inclusion and pertinence to this panel.Created: 20 Jul 2017, 2:05 p.m.
added new-gene-name tag, new approved HGNC gene symbol is SPARTCreated: 19 Jul 2017, 4:29 p.m.
Phenotypes for gene: SPART were changed from Troyer syndrome; MIM:275900; developmental delay to Troyer syndrome, OMIM:275900
Source: Expert Review Amber was removed from gene: SPART
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.
Phenotypes for SPART were set to Troyer syndrome; MIM:275900; developmental delay
Expert Review Green was added to SPART. Panel: Intellectual disability Publications for gene SPART was set to ['18413476', ' 20437587', ' 26003402', ' 28679690']
SPG20 was changed to SPART
new-gene-name was removed from SPG20. Panel: Intellectual disability
This gene has been classified as Amber List (Moderate Evidence).
SPG20 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene
SPG20 was created by BRIDGE
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.