Bone Marrow Failure

Gene: POLA2

Green List (high evidence)

New gene-disease association.

PMID: 39616267 - Five individuals from two unrelated swedish families presenting with clinical phenotype suggestive of a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Affected individuals also presented with shortened telomeres.

Compound heterozygous variants were identified in both families.
Family A (Ile96Thr;Pro424Leu) - Both variants are present in gnomAD v4.1 but FAF is rare enough for AR condition [c.287 T > C, p.(Ile96Thr) - FAF 0.002%; c.1271 C > T, p.(Pro424Leu) - FAF 0.0002 %]
Family B (Ile96Thr; intragenic SNV resulting in the deletion of the 5’ terminal and exon 1) - same missense as the other family along with an SNV.

In vitro assay using CRISPR/Cas9 genome engineering into HEK293T to assess whether the p.(Ile96Thr) would affect telomere length. The subclones carrying the missense variant showed telomeric shortening of ~4kb compared to the WT subclones.
Sources: Literature

Created: 5 Dec 2024, 10:37 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Telomere biology disorders; Coats plus syndrome MONDO:0012815

Publications

• 39616267