Submission Details

The CDC45 gene is located on chromosome 22 at 22q11.21 and encodes cell division cycle 45 protein, a DNA polymerase required for DNA replication initiation. CDC45 was first reported in relation to autosomal recessive Meier-Gorlin syndrome in 2016 (Fenwick et al., PMID: 27374770). Characteristic features for this disorder include craniosynostosis, microtia, short stature, and absent or small patellae. Additional features include microcephaly, Chiari malformation, mild to severe developmental delay, facial dysmorphism, cleft palate, feeding difficulties, anorectal malformations, joint laxity, delayed bone age, genital anomalies, gastro-esophageal reflux, syndactyly, digital clubbing, proptosis, thin eyebrows, ventricular septal defects, and hearing loss. At least 21 variants (including frameshift, stop-gained, intragenic deletion, splice region, and missense variants) have been reported in 14 individuals from four publications (PMID: 27374770; Ting et al., 2019, PMID: 30986546; Knapp et al. 2021, PMID: 33639314; Li et al. 2021, PMID: 34000999) and are included in this curation. The mechanism of pathogenicity is presumed to be loss of function. This gene-disease relationship is also supported by an animal model and biochemical function (Yoshida et al., 2001, PMID: 11416137; Guernsey et al., 2011, PMID: 21358631). In summary, CDC45 is definitively associated with autosomal recessive Meier-Gorlin syndrome. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 05Oct2022 (SOP Version 9).