Submission Details

Biallelic MALT1 germline loss of function variants were first identified in two siblings with combined immunodeficiency (CID) in 2013 (PMID: 23727036). Autosomal recessive MALT1 deficiency is associated with a combination of recurrent bacterial, viral, or fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. Immunological defects are variable, but typically include normal total T lymphocyte numbers, impaired B cell development with normal/decreased numbers, and variable eosinophilia. There is impaired T cell mitogen proliferation and reduction in Foxp3+ regulatory CD4 T (Treg) cells as well as T helper 17 (TH17) cells. 11 variants have been reported and are composed of missense, frameshift, splice site and indel variants resulting in the loss of function of MALT1. Evidence supporting this gene-disease relationship includes case-level and experimental data. 7 unique variants from 7 individuals across 6 publications were curated (PMID: 23727036, 27253662, 24332264, 31037583, 32858082, 25627829). Heterozygous carriers have not been shown to have a clinical phenotype. More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts).

Experimentally, in vitro studies studying MALT1 function use patient derived cells to support this gene-disease relationship. MALT1 is a paracaspase that regulates antigen receptor signaling pathways in lymphocytes. In response to antigen receptor signaling, -MALT1 serves as a scaffold protein for BCL10 and associates with CARD family proteins to generate the CBM signalosome complex. This CBM complex recruits signaling intermediates that lead to the activation of the NF-kB, c-Jun N-terminal kinase (JNK) and the mechanistic target of rapamycin (mTOR) pathways. The MALT1 protein has been shown to be expressed in T and B lymphocytes and is absent in patients with biallelic MALT1 variants with associated CID (PMID:30692685). In vitro functional data demonstrates altered NF-kB signaling in patient cells with MALT1 variants, with associated changes in downstream activation, proliferation, and cytokine production in lymphocytes (PMID:30692685). Mouse models of MALT1 deficiency or alterations of the protease domain show defects in generation and maintenance of B and T lymphocytes, alterations in Foxp3+ regulatory T cell development and alterations in serum immunoglobulin levels (PMID:14576442, 26405015, 25762782). These phenotypic changes are associated with alteration in NF-kB signaling, replicating those defects seen in patients. In summary, MALT1 is definitively associated with combined immunodeficiency. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

This classification was approved by the ClinGen SCID-CID Working Group on 7/21/2022 (SOP Version 9).