Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: IKZF3

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 10:59 a.m. | Last Modified: 8 Mar 2022, 10:59 a.m.

Panel Version: 2.532

Comment on list classification: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.

Created: 15 Nov 2021, 12:17 p.m. | Last Modified: 15 Nov 2021, 12:20 p.m.

Panel Version: 2.493

Comment on mode of pathogenicity: Variants discovered to date located in DNA binding domain of IKZF3/AIOLOS, with dominant-negative effect on WT.

Created: 15 Nov 2021, 12:17 p.m. | Last Modified: 15 Nov 2021, 12:17 p.m.

Panel Version: 2.491

Comment on list classification: New gene added by Boaz Palterer (University of Florence). Rating Red as only a single family with B cell deficiency has been reported at this time. Includes supportive mouse model showing B cell developmental defects and T cell abnormalities (PMID:34155405).

Created: 29 Jun 2021, 9:22 a.m. | Last Modified: 29 Jun 2021, 9:22 a.m.

Panel Version: 2.435

Red List (low evidence)

New kindred with 4 affected subjects reported with autosomal dominant IKZF3 variant ( p.N160S ) by Kuehn et al.

Created: 27 Oct 2021, 10:30 a.m. | Last Modified: 27 Oct 2021, 10:30 a.m.

Panel Version: 2.480

Motoi Yamashita et al. ( https://www.nature.com/articles/s41590-021-00951-z ) identified 3 patients from a kindred harboring the missense G159R variant in AIOLOS, encoded by the IKZF3 gene. They demonstrated that the variant acts as a dominant-negative mutation through heterodimeric interference by disrupting IKAROS (IKZF1) function.
Sources: Literature

Created: 22 Jun 2021, 10:43 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
B cell deficiency; EBV inefctions suspectibility; hypogammaglobulinemia; T and B cell abnormalities; pneumocystis pneumonia; chronic lymphocytic leukemia

Publications

• 34694366, 34155405