Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: IVNS1ABP

I don't know

Comment on list classification: Rating Amber in view of the possibility of incomplete penetrance, and uninformative segregation analysis in 2/3 cases. Awaiting additional publications/clinical evidence to validate association (added to watchlist).

Created: 11 Aug 2020, 2:20 p.m. | Last Modified: 11 Aug 2020, 2:20 p.m.

Panel Version: 2.184

PMID: 32499645 (2020) - Three unrelated families with LOF variants (1 intragenic deletion, 2 distinct nonsense variants) in the IVNS1ABP gene. All affected patients presented with an immunologic disorder characterised by severe recurrent cutaneous warts on the hands, feet, and face. Additional variable features of immunodeficiency and autoinflammation included recurrent infections, colitis, and retinal vasculitis. Laboratory studies showed that all variant carriers exhibited low CD4+ T cells and numbers of total T cells and B cells towards the lower limit of the normal range. Western blot analysis showed a ~50% reduction of IVNS1ABP protein in patient peripheral blood cells compared to control individuals, consistent with haploinsuffiency.

In kindred A, the mother of the proband also carried the variants - she did show a low CD4+ T cell and CD19+ B cell count; however, she did not have a history of infection. Therefore, the possibility of incomplete penetrance should be considered. In kindred B, the variant was not present in the unaffected father or brother; the mother was not available for genetic investigation. In kindred C, neither parent was available for investigation.

Created: 10 Aug 2020, 2:27 p.m. | Last Modified: 10 Aug 2020, 2:27 p.m.

Panel Version: 2.175

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Immunodeficiency 70, 618969

Publications

• 32499645

Green List (high evidence)

3 unrelated families with putative loss of function variants. Case features and immunophenotyping of patient cells is suggestive of a combined immune deficiency, based on the ESID definitions of PID subtypes.

Created: 3 Aug 2020, 11:04 a.m. | Last Modified: 3 Aug 2020, 11:04 a.m.

Panel Version: 2.175

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Immunodeficiency 70, MIM#618969

Publications

• 32499645

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988)

Created: 26 May 2020, 8:36 a.m. | Last Modified: 26 May 2020, 8:36 a.m.

Panel Version: 2.175

Mode of inheritance
Unknown

Phenotypes
primary immunodeficiency

Publications

• https://doi.org/10.1101/499988