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Intellectual disability

Gene: POLA1

Green List (high evidence)

POLA1 (DNA polymerase alpha 1, catalytic subunit)
EnsemblGeneIds (GRCh38): ENSG00000101868
EnsemblGeneIds (GRCh37): ENSG00000101868
OMIM: 312040, Gene2Phenotype
POLA1 is in 4 panels

5 reviews

Rebecca Foulger (Genomics England curator)

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.

Konstantinos Varvagiannis (Other)

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

Louise Daugherty (Genomics England Curator)

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

Caroline Wright (Sanger)

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)

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
Phenotypes
  • Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220
  • XLPDR
  • X-Linked Intellectual Disability associated with short stature, microcephaly, and hypogonadism
OMIM
312040
Clinvar variants
Variants in POLA1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

10 Jun 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: pola1 has been classified as Green List (High Evidence).

10 Jun 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: POLA1 were set to 15844784; 27019227; 19377476

10 Jun 2019, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

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 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.

5 Jan 2018, Gel status: 1

Set mode of inheritance, Set publications

Ellen McDonagh (Genomics England Curator)

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']

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)

POLA1 was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

POLA1 was created by ellenmcdonagh