Severe microcephalyGene: PRIM1
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.
Created: 31 Mar 2021, 10:24 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Microcephalic primordial dwarfism, MONDO:0017950
Gene: prim1 has been classified as Amber List (Moderate Evidence).
Tag watchlist was removed from gene: PRIM1. Tag Q2_21_rating tag was added to gene: PRIM1.
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