Submission Details

PRIM1 was first reported in relation to autosomal recessive primordial dwarfism-immunodeficiency-lipodystrophy (PDIL) syndrome in 2020 (Parry DA et al., PMID: 33060134). PDIL syndrome is characterized by unique facial features, prenatal and postnatal growth restriction, immunodeficiency disorder (recurrent infections, low IgM, low IgA, or B cell deficiency), chronic respiratory syndrome, and hepatic dysfunction.

A total of 4 variants (3 splicing and 1 missense) have been reported in eight probands from six families in two publications that were included in this curation (PMIDs: 33060134, 38773012). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Since 2020, there has been one splicing variant recurrently reported in six probands: four of them were from the same country and all were homozygous for this variant (PMIDs: 33060134, 38773012). A different splicing variant was reported in the compound heterozygous state alongside a missense variant in one proband (PMID: 33060134). In 2024, a third novel splicing variant was reported in the homozygous state in one proband with a relatively mild clinical phenotype but pronounced B cell lymphopenia (normal T cell count) and no evidence of developmental issues or liver disease (PMID: 38773012). The genetic evidence score reached 9 after variant scores were curated with incorporation of experimental evidence that suggests the two canonical splicing variants resulting in in-frame insertion proteins are hypomorphic. In all reported cases, parents who carry a heterozygous PRIM1 variant are clinically unaffected.

This gene-disease relationship is also supported by experimental evidence (e.g. expression, in vitro functional assays, yeast models, etc.) (PMIDs: 33060134, 38773012). Partial loss of PRIM1 protein was demonstrated on immunoblotting of lymphoid and fibroblast cells from patients with the recurrent homozygous splicing variant (PMIDs: 33060134, 38773012). In one of the patients carrying the identical recurrent homozygous splicing variant, doubling time in their fibroblasts appeared increased compared to controls and impaired efficiency of DNA replication was observed in BrdU-DNA content flow cytometry (PMID: 33060134). To investigate the effect of the missense variant, a non-patient cell functional assay was performed and demonstrated partial loss of PRIM1 protein likely due to misfolding and/or disturbance of the catalytic site (PMID: 33060134). To further investigate the same missense variant, a yeast model study was complete and found defects in DNA synthesis which resulted in lethality for yeast (PMID: 33060134). For the other splicing variant reported in 2020, in vitro functional assay exemplified evidence of lower PRIM1 protein levels, consistent with the partial loss of function (PMID: 33060134). In the cells of the patient reported in 2024 with a similar novel splicing variant and more pronounced B cell lymphopenia phenotype but less clinical severity, a partial loss of PRIM1 protein was observed (PMID: 38773012). PRIM1 is involved in DNA synthesis alike POLE which has also been associated with immunodeficiency (PMID: 24043831).

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

This classification was approved by the ClinGen SCID-CID GCEP on the meeting date March 20, 2025 (SOP Version 11).