Intellectual disability - microarray and sequencing
Gene: POLA1 Green List (high evidence)Comment on list classification: Updated rating from Red to Green based on additional 2019 paper provided by Konstantinos Varvagiannis. PMID:31006512 (Van Esch et al., 2019) report 9 additional males from 5 families hemizygous for POLA1. ID or DD was a feature in all patients (Table 1) and is seen alongside short stature, microcephaly and hypogonadism. The phenotype was distinct from the previously-reported XLPDR. Although the phenotype spectrum is broad for POLA1 variants, there are sufficient cases of ID/DD (>3 from PMID:31006512 and PMID:27019227, with ID/DD being a consistent phenotype in PMID:31006512 individuals), thereby warranting a Green rating.Created: 10 Jun 2019, 9:24 a.m.
Green List (high evidence)
Further evidence (Van Esch et al. 2019 - PMID: 31006512) supports upgrade of this gene to green or amber. In summary 9 affected males (from 5 families) hemizygous for POLA1 mutations, private to each family, have been reported. ID (mild (4), moderate (3), severe (1)) was a feature in most.
De novo occurrence in 2 subjects, segregation studies in larger families, skewing of inactivation in heterozygous females (all probably unaffected), effect of some variants (on splicing, mRNA and/or protein levels) and demonstration of replication deficits in proband lymphoblastoid cell lines under conditions of replication stress (3 variants evaluated) or spontaneously during unperturbed, exponential growth (1 variant) [POLA1 encoding the catalytic subunit of the DNA polymerase α-primase] are among the arguments provided.
Overlapping features consisted of DD/ID, growth failure, microcephaly, hypogonadism with additional (eg. GI or cardiovascular) abnormalities reported in few. The phenotype did not correspond to that of XLPDR (an intronic POLA1 variant previously reported in 12 unrelated relevant families) with only one individual having recurrent infections as a suggestive feature. POLa levels were also different between the 2 disorders, although this was evaluated in fibroblasts from only 2 respective subjects (one with ID and one with XLPDR).
Van Esch et al. parallel the broad phenotypical spectrum associated with POLA1 mutations to that of POLE (FILS syndrome and IMAGE-I, MIM 615139 and 618336). The phenotype of the POLA1 associated disorder (microcephaly, growth failure) is thought to be consistent with that of other disorders affecting components of the DNA replication machinery.
The variants reported to date in individuals with ID include the following (NM_016937.3): c.236T>G (p.Ile79Ser) / c.4142C>T (p.Pro1381Leu) / c.507+1G>A (2 abnormal transcripts leading to Lys149_Glu169del and Thr170_Ser1462delins15* at the protein level) / c.445_507del (p.Lys149_Glu169del) / c.328G>A (p.Gly110Arg - also affecting the last nt of exon 4).
POLA1 is included in gene panels for ID offered by some diagnostic laboratories. The gene is not part of the DD panel of G2P. Pigmentary disorder, reticulate, with systemic manifestations, X-linked (MIM 301220) is the only POLA1-related phenotype listed in OMIM but as has been commented on in the previous review (and discussed by Van Esch et al.) affected individuals do not exhibit ID.Created: 26 Apr 2019, 7 a.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Hypogonadism
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
From PMID: 27019227 (2012) In affected members of 12 unrelated families with X-linked PDR, a intronic mutation, hemizygous (in males) or heterozygous (in females) was idenitified in the POLA1 gene. All affected individuals carried the same mutation. The clinical phenotype of the patient cohort was accessed and only two cases were reported with developmental delay phenotype (cases from Dallas, Canada), but there is an additional unrelatedcase from Waco denoted with Failure to thrive phenotype. Discussed with clinical team, failure to thrive is a term used to indicate poor growth in childhood (height / weight at the bottom of / below the normal range) therefore not relevant to ID.Created: 18 Dec 2017, 3:39 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR
Publications
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)
Red List (low evidence)
Gene: pola1 has been classified as Green List (High Evidence).
Publications for gene: POLA1 were set to 15844784; 27019227; 19377476
Phenotypes for gene: POLA1 were changed from Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR to Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR; X-Linked Intellectual Disability associated with short stature, microcephaly, and hypogonadism
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.
Model of inheritance for gene POLA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene POLA1 was set to ['15844784', '27019227', '19377476']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
POLA1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
POLA1 was created by ellenmcdonagh
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.