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Severe microcephaly

Gene: PRIM1

Amber List (moderate evidence)

PRIM1 (DNA primase subunit 1)
EnsemblGeneIds (GRCh38): ENSG00000198056
EnsemblGeneIds (GRCh37): ENSG00000198056
OMIM: 176635, Gene2Phenotype
PRIM1 is in 2 panels

1 review

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is sufficient evidence to rate this gene Green at the next review
Created: 12 Apr 2021, 3:57 p.m. | Last Modified: 12 Apr 2021, 3:57 p.m.
Panel Version: 2.111
PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype.

- PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Created: 31 Mar 2021, 10:24 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephalic primordial dwarfism, MONDO:0017950

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Microcephalic primordial dwarfism, MONDO:0017950
Tags
Q2_21_rating
OMIM
176635
Clinvar variants
Variants in PRIM1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

12 Apr 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: prim1 has been classified as Amber List (Moderate Evidence).

12 Apr 2021, Gel status: 1

Removed Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist was removed from gene: PRIM1. Tag Q2_21_rating tag was added to gene: PRIM1.

31 Mar 2021, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Arina Puzriakova (Genomics England Curator)

gene: PRIM1 was added gene: PRIM1 was added to Severe microcephaly. Sources: Literature watchlist tags were added to gene: PRIM1. Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRIM1 were set to 33060134 Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950 Review for gene: PRIM1 was set to AMBER