Biallelic DNMT3B germline hypomorphic variants were first reported in relation to immunodeficiency, centromere instability and facial anomalies syndrome type 1 (ICF1) in 1999 (PMID: 10555141, 10588719, 1064701). Patients with ICF1 exhibit a distinct cytogenetic abnormality characterized by multiradiate chromosomes derived from stimulated lymphocytes, comprising chromosomes 1, 9, and 16. This syndrome is associated with mild facial dysmorphisms, recurrent and opportunistic infections, altered T cell CDR3 length and impaired development of B cells associated with hypo- or agammaglobulinemia. 23 variants were curated and are composed of missense, nonsense, frameshift, and splice site mutations. Complete deficiency of DNMT3B is embryonic lethal, thus pathogenic mutations are hypomorphic (PMID: 16501171). Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous carriers have not been shown to have a clinical phenotype or biochemical changes associated with patients with ICF1 (PMID: 28117327). More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts).
DNMT3A and DNMT3B are DNA methyltransferases involved in de novo DNA methylation. DNMT3B, which is expressed in various tissues, plays a critical role in embryonic development and is responsible for methylation of minor satellite repeat regions. In patients with ICF1, DNA methylation is markedly disrupted (PMID: 10555141, 10647011). While the exact mechanism of immune defect is unknown in ICF patients, B cells in ICF patients show abnormal development and the absence of isotype class switched cells (PMID: 14645008). Analysis of T cell receptor usage by T cells also suggests altered T cell development and selection (PMID: 34825286). In ICF1 patient derived induced pluripotent cells (iPSCs), reversion of the DNTM3B mutations resulted in the reacquisition of normal methylation of pericentromeric repeats, with only partial methylation seen in subtelomeric repeats (PMID: 31738163). A mouse model of ICF showed facial abnormalities, impaired T cell development and global DNA methylation defects (PMID: 16501171). These model phenotypic changes replicated some defects seen in patients. In summary, there is definitive evidence to support this gene-disease relationship. 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 4/16/2023 (SOP Version 9).
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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