LRBA

Inheritance Pattern: AR

Disease ID:MONDO:0013863

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013863

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0013863

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013863

Submitter: ClinGen

*LRBA* (LPS Responsive Beige-Like Anchor Protein) gene variants linking common variable immunodeficiency-like phenotype and LRBA deficiency were first reported in 2012 (PMIDS: 22608502 and 22721650). LRBA deficiency is also referred to as LATAIE disease (LRBA deficiency with autoantibodies, Treg defects, autoimmune infiltration, enteropathy) (PMID: 27418640). This disease, in contrast with its counterpart, CTLA4 haploinsufficiency (CHAI syndrome) is nearly completely penetrant though shows substantial variable expressivity (PMID: 34384744). The mechanism of pathogenicity is reported to be biallelic loss of function leading to variable phenotypes of severe immune dysregulation due to loss of immune checkpoint function, organomegaly, and recurrent infections (PMID: 26768763). Evidence from 5 probands in 4 publications were included in this curation (PMID: 22608502, PMID: 22721650, PMID: 25468195 and PMID: 32154999) representing 6 (missense, frameshift, and nonsense) variants. A case report of uniparental isodisomy is included as an unscored evidence with a severe lethal phenotype (PMID: 30386343). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Experimental evidence also supports this gene disease association. LRBA-deficient patients show disturbed B cell function with production of low levels of IgG and reduced ability to induce autophagy in response to starvation compared to control cells (PMID: 22608502). Impaired function of regulatory T cells (Tregs/TR) cells is evident by a markedly reduced number of CD4+FOXP3+ TR cells and decreased suppression of T cell proliferation in LRBA-deficient patients (PMID: 25468195). LRBA is detected to colocalize with cytotoxic T-lymphocyte-associated protein-4 (a known inhibitor of immune responses by negative signaling) in endosomal vesicles and LRBA deficiency or knockdown resulted in increased CTLA4 turnover (PMID: 26206937). In patients, assessment of CTLA4 transendocytosis is helpful in making the diagnosis (PMID: 28159733) in conjunction with assessment LRBA protein expression by flow cytometry (PMID: 29740429), which is not always helpful as an independent diagnostic assay. The relevance of LRBA chaperone function in maintaining CTLA4 expression in Tregs is evident from the response to exogenous CTLA4 therapy (abatacept) in patients with both LRBA deficiency and CTLA4 haploinsufficiency (PMID: 26206937 and PMID: 31238161). Murine Lrba knockout model showed decreased CTLA-4 expression by regulatory T cells and activated conventional CD4+ and CD8+ T lymphocytes. It was able, nonetheless, to produce normal serum immunoglobulin M (IgM) and IgG with no evidence of clinical or immunological signs of disease (PMID: 28652580). While more experimental evidence is needed to understand the redundant gene function in the mouse model, other experimental evidence (expression, protein interaction, and disturbed immune cells' functions in LRBA-deficient patients) supported the genetic case-level evidence and provided the required score for a definitive classification. The first cases of early-onset diabetes in patients with bi-allelic loss of function (LOF) variants in LRBA and immune dysregulation were reported in 2016 (PMID: 26745254). When diabetes is the presenting feature in LRBA deficiency, it is most often diagnosed in infancy, similar to other causes of neonatal diabetes but sometimes with antibodies present (PMID: 35453810). In contrast, LRBA cases with presentations that do not include diabetes tend to be diagnosed at later ages. While all pathogenic variants in LRBA appear to be LOF, the variants in cases with diabetes often cause significant protein truncation, such as introduction of stop codons, or large deletions often involving several exons (PMID: 26745254, 28473463, 33845048, 36078750, 33912197). Finding bi-allelic P/LP LRBA variants on a sequencing panel in an individual with diabetes should prompt awareness of the possibility of the development of other systemic problems such as other autoimmune conditions, enteropathy, immunodeficiencies and growth failure, among other less common features. Similarly, in individuals discovered to have P/LP LRBA deficiency due to P/LP bi-allelic LOF variants but who have not been diagnosed with diabetes, glucose monitoring is advised, based on the ~30% prevalence (PMID: 31887391) of neonatal diabetes in this disorder. It has been proposed (PMID: 35453810) that the diabetes in LRBA deficiency is due to beta-cell dysfunction rather than autoimmunity based on the observation that blood transcriptomic analysis comparing an individual with LRBA-deficiency with pooled healthy controls revealed no differences in the expression of gene modules related to autoimmunity diseases. They also showed siRNA knockdown of LRBA in mouse pancreatic beta-cells reduced cellular proinsulin and insulin secretion without affecting cell viability. However, the presence of sibships with LRBA deficiency discordant for diabetes argues against a beta-cell vs. autoimmune etiology (PMID: 37443020) Further long-term study will be needed to determine whether diabetes will only be seen in certain severely truncating variants, or if it may occur later in life in those with variants causing presentations of LRBA deficiency that did not initially include diabetes. In summary, the evidence to support the relationship of LRBA deficiency due to *LRBA* gene and CVID-like phenotype is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been held up overtime. This classification was approved by the ClinGen Antibody Deficiency GCEP on May 5th, 2022 (SOP Version 8). The amendment proposed by the Monogenic Diabetes GCEP was approved and submitted by the ClinGen Antibody Deficiency GCEP on January 6th, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0013863

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013863

Submitter: PanelApp Australia