B2M was first reported in relation to B2M deficiency, initially referred to as autosomal recessive familial hypercatabolic hypoproteinemia (FHH) in 2006 (Wani et al., PMID: 16549777). B2M deficiency is characterized by hypoproteinemia, hypogammaglobulinemia, decreased immune cells (B cells, NK cells, and alpha-beta T cells), abnormal skin lesions including granulomatous dermatitis and ulcerations, bronchiectasis, and limb anomalies. The mechanism of pathogenicity appears to be homozygous loss of function.
The curation of B2M related to B2M deficiency includes both case-level and experimental evidence. Two variants (missense and splice site) have been reported two probands in two publications (PMID: 16549777, 25702838) are included in this curation. Heterozygous carriers were not identified to have any clinical features associated with B2M deficiency. This gene-disease relationship is also supported by recapitulation of decreased T cells and absent cell surface expression of MHC-1 in a B2M-null mouse model (PMID: 2112266), lack of expression of the B2M protein along with other MHC-I proteins including neonatal Fc receptor (FcRn) protein in patient derived cells (PMID: 25702838), and the reduced full length mRNA expression using RT-PCR in an individual with confirmed canonical splice site mutation and B2M deficiency in serum (PMID: 25702838). These results support the role of B2M in the development and function of major histocompatibility complex-I (MHC-I), an important component of the immune response system.
In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
Of note, this gene has also been implicated in autosomal dominant familial visceral amyloidosis. At this time, there has only been a single published report of a variant in B2M in an individual with amyloidosis (PMID: 22693999). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in the reported mechanism, inheritance, and phenotype of the reported individual with amyloidosis and those reported with B2M deficiency. However, more information is needed regarding these two conditions to assess if they should be lumped or split. At the time of this curation, these disease entities will be treated as split, and only B2M deficiency will be assessed.
This classification was approved by the ClinGen SCID/CID Gene Curation Expert Panel on the meeting date 3/21/2021 (SOP Version [10]).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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