SLX4 encodes a protein that functions as a scaffold element for the assembly of a multiprotein complex containing endonucleases activity required for repair of specific types of DNA lesions and critical for cellular responses to replication fork failure. SLX4 was first reported in relation to autosomal recessive inheritance and Fanconi anemia complementation group P in 2011 (Kim Y et al., PMID: 21240275; Stoepker C et al., PMID: 21240277). Fanconi anemia is a rare hereditary disease characterized by genomic instability, developmental abnormalities, bone marrow failure and cancer predisposition, mainly leukemia and solid tumors. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split autosomal dominant hereditary breast cancer into separate curations due to phenotypic variability and different inheritance patterns. Therefore, this curation solely focuses on autosomal recessive FANCP. The mechanism of pathogenicity is loss of function. Ten variants (including nonsense, frameshift, and intronic) that have been reported in six probands in three publications (PMIDs: 21240275, 21240277, 36463940) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease relationship is also supported by experimental evidence from animal and cell models (3 Points, PMID 21240275, 21240276). Mice with knockout of Btbd12, the mouse ortholog of SLX4, recapitulated many key features of the human Fanconi anemia, for example Btbd12-deficient animals were born at sub-Mendelian ratios, had greatly reduced fertility, were developmentally compromised and were prone to blood cytopenias. In addition, although expression of wildtype SLX4 fully rescued the FA phenotypes in fibroblasts derived from FA patients carrying biallelic SLX4 variants, mutant SLX4 proteins failed to rescue these phenotypes. In summary, there is definitive evidence supporting the relationship between SLX4 and autosomal recessive inheritance Fanconi anemia, complementation group P. This 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 Hereditary Cancer GCEP on the meeting date of October 27, 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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