Submission Details

The ANAPC1 gene, located on chromosome 2 at 2q13, encodes anaphase promoting complex subunit 1, which is a component of the anaphase promoting complex/cyclosome (APC/C). ANAPC1 was first reported in relation to autosomal recessive Rothmund-Thomson syndrome type 1 in 2019 (Ajeawung et al., PMID: 31303264). Rothmund-Thomson syndrome type 1 is a subform of Rothmund-Thomson syndrome (RTS) presenting with a characteristic facial rash (poikiloderma) and is frequently associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, and rapidly progressive bilateral juvenile cataracts. Patients may also have growth retardation and genital, skeletal, and dental abnormalities but do not appear to have an increased risk of developing cancer. At least 11 patients from eight families have been described (PMID: 31303264, 35664819). Five variants (1 recurrent intronic, 2 frameshift, 1 canonical splice, and 1 large deletion) reported in eight unrelated probands in two publications (PMID: 31303264, 35664819) are included in this curation. Please note that 0.5 pts were awarded for the recurrent intronic variant observed in trans with the large deletion, which could not be entered, resulting in a total of 8.5 genetic evidence points. Co-segregation of ANAPC1 variants was observed in three affected family members from three families, including from the Plain community; however, none of the families met the criteria to score segregation. Notably, a deep intronic variant, c.2705-198C>T, which has been shown to result in the inclusion of a pseudoexon and introduction of a premature truncation codon, has been identified in every patient described to date. The mechanism of pathogenicity may involve loss of function, as suggested by reduced ANAPC1 mRNA and protein expression in patient fibroblasts, but additional investigation is needed. This gene-disease relationship is also supported by experimental evidence, including a biochemical function in cell cycle regulation, DNA repair and replication, and chromosomal and genomic stability that is shared with at least one gene associated with a similar phenotype; evidence of a cell cycling defect in patient fibroblasts; and an increased rate of cataract development in heterozygous knockout mice (PMID: 31303264). In summary, there is moderate evidence supporting the relationship between ANAPC1 and autosomal recessive Rothmund-Thomson syndrome type 1. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on September 20, 2024 (SOP Version 11).