Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: RAP1B

Red List (low evidence)

Comment on list classification: Only one recent case from PMID:39225097 (2024) presented with combined immunodeficiency in addition to thrombocytopenia and other previously reported phenotypes. The variant from this patient was somatic rather than germline. So, the 'somatic' tag has been added.

All the other cases were reported with thrombocytopenia and congenital anomalies. Hence, this gene should be rated red on this panel.

Created: 24 Oct 2025, 4:19 p.m. | Last Modified: 24 Oct 2025, 4:19 p.m.

Panel Version: 8.59

Comment on phenotypes: OMIM phenotype accessed on 24 October 2025

Created: 24 Oct 2025, 4:15 p.m. | Last Modified: 24 Oct 2025, 4:15 p.m.

Panel Version: 8.58

PMID:32627184 (2020) reported the identification of two novel de novo heterozygous missense variants in two unrelated patients with syndromic thrombocytopenia with multiple malformations, microcephaly, learning difficulties, dysmorphism and other features. It is also hypothesised that these variants contribute to disease phenotypes through a gain-of-function mechanism.

PMID:35451551 (2022) reported a 23‐year‐old male with a novel de novo missense gain‐of‐function variant in RAP1B gene. This patient also presented with RAP1B‐related syndromic thrombocytopenia.

PMID:37850357 (2024) reported the identification of de novo heterozygous missense variants in RAP1B gene in two unrelated individuals thrombocytopenia, as well as congenital malformations, and neurological, behavioural, and dysmorphic features.

PMID:39225097 (2024) reported a patient with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a de novo heterozygous missense variant (p.Gly12Glu) in RAP1B gene. The study demonstrated the mechanism of this variant as well as two previously demonstrated variants (p.Gly12Val and p.Gly60Arg) as gain-of-function. In addition, pGly12Glu variant was shown to be a somatic variant in the patient whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations.

Created: 24 Oct 2025, 4:14 p.m. | Last Modified: 24 Oct 2025, 4:14 p.m.

Panel Version: 8.56

Mode of inheritance
Other

Phenotypes
Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, MONDO:0958000

Publications

• 32627184
• 35451551
• 37850357
• 39225097

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Heterozygous mutation in RAP1B are associated with Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies ( OMIM #620654 ).

Variants have been shown to be gain of function.
Wide spectrum of disease presentation, germline variants associated with full spectrum of disease, reported somatic variants presenting with isolated hematological disease. Varying degree of immunodeficiency, leukopenia and lymphopenia, relevant to this panel.
Sources: Literature

Created: 14 Apr 2025, 8:01 p.m.

Mode of inheritance
Other

Phenotypes
thrombocytopenia; leukopenia; lymphopenia; anemia; splenomegaly; immunodeficiency; preauricular tag; upslanting palpebral fissures; flat midface; scarce eyebrows; low-set and posteriorly rotated ears; hypoplastic teeth; umbilical hernia, and genitourinary abnormalities; hydronephrosis; vesicoureteral reflux; unilateral cryptorchidism

Publications

• 39225097

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments