Intellectual disability - microarray and sequencing
Gene: PITRM1 Green List (high evidence)Comment on list classification: PITRM1 identified by expert review by Konstantinos Varvagiannis. Currently no OMIM or G2P terms association. PMID: 29764912 reports on 2 consanguineous Palestinian families each with 2 affected boys. Both Palenstinian families are from Arab descent but are from different locale. PMID: 26697887 reports 2 siblings from a consanguineous Norwegian family homozygous for a missense variant (NM_014889.2:c.548G> or p.Arg183Gln). Although there is some functional work (PMID: 29383861) phenotypes are varied in severity. However sufficient unrelated families (>3) for PITRM1 to be classified as Green.Created: 29 May 2019, 9:45 a.m.
Green List (high evidence)
Biallelic pathogenic variants in PITRM1 seem to be associated with a phenotype of DD/ID and spinocerebellar ataxia.
6 individuals from 3 unrelated families have been reported.
PMID: 26697887 reports on 2 individuals from a consanguineous Norwegian family homozygous for a missense variant (NM_014889.2:c.548G> or p.Arg183Gln).
PMID: 29764912 reports on 2 consanguineous Palestinian families each with 2 affected boys. All affected individuals for both families were homozygous for a further missense variant (p.Thr931Met).
The boys from one Palestinian family appeared to be more severely affected - compared to the sibs from the other family with the same variant - due to a concurrent X-chromosome rearrangement.
Pathogenicity is supported by extensive functional studies performed in both articles as well as an additional one (PMID: 29383861) on Arg183Gln.
PITRM1 is included in gene panels for ID offered by (few) diagnostic laboratories.
The gene is not associated with any phenotype in OMIM nor in G2P.
As a result, PITRM1 can be considered for inclusion in the ID panel as green (or amber).
Sources: LiteratureCreated: 14 Dec 2018, 2:51 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability; Ataxia
Publications
Variants in this GENE are reported as part of current diagnostic practice
Tag gene-checked tag was added to gene: PITRM1.
Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Source Expert Review Green was added to PITRM1. Source Expert Review was added to PITRM1. Added phenotypes Ataxia; Intellectual disability for gene: PITRM1 Rating Changed from No List (delete) to Green List (high evidence)
gene: PITRM1 was added gene: PITRM1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PITRM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PITRM1 were set to 26697887; 29764912; 29383861 Phenotypes for gene: PITRM1 were set to Intellectual disability; Ataxia Penetrance for gene: PITRM1 were set to Complete Review for gene: PITRM1 was set to GREEN gene: PITRM1 was marked as current diagnostic
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.