Submission Details

The CDT1 gene is located on chromosome 16 at 16q24.3 and encodes the chromatin licensing and DNA replication factor 1, a ubiquitously expressed protein which is required for pre-replication complex assembly. The CDT1 cooperates with the origin recognition complex (ORC) and CDC6 in recruiting mini-chromosome maintenance (MCM) complex to DNA to form pre-replication complexes and is also implicated in mitosis. The CDT1 gene was first reported in relation to autosomal recessive Meier-Gorlin syndrome 4 (MGS4) in 2011 (Bicknell et al. 2011 PMID 21358632; Guernsey et al. 2011 PMID 21358631). Meier-Gorlin syndrome (MGS) is characterized by a clinical triad of symptoms: short stature, microtia, and small or absent patellae. Additional features reported in individuals with MGS4 may include IUGR with failure to thrive, reduced body weight, respiratory issues, pulmonary emphysema, abnormal genitalia in males and mammary hypoplasia in females, musculoskeletal abnormalities, and dysmorphic facial features with small mouth, microretrognathia, and full lips, among other presentations (22333897: de Munnik et al. 2012). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least nine unique variants have been found in either compound heterozygous (n=7) or homozygous (n=1) state in eight cases diagnosed with MGS from five reports in the literature (21358631; 21358632; Munnik et al., 2012 PMID 22333897; Kim et al. 2017 PMID 28425089; Knapp et al. 2020 PMID 33338304). These included four unique missense variants (one of which is is predicted to impact splicing), two nonsense variants, one frameshift variant, one intronic variant shown to affect splicing, and one in frame indel (removing 1 amino acid) variant. More genetic evidence has been reported in the literature but was not scorable according to the current guidelines (21358632; 28425089; Fitzgerald et al. 2015 PMID 25533962; Retterer et al. 2016 PMID 26633542). Experimental evidence includes data on biochemical function, functional alteration and a non-human model organism. A number of genes involved in pre-replication complex formation and function have been associated with Meier-Gorlin syndrome (MGS). Specifically, ORC1, ORC4, ORC6, CDC6, CDC45, MGM5, GMNN, and DONSON have all been associated with autosomal recessive MGS (33477564: Schmit and Bielinsky 2021). Patient-derived lymphoblastoid cell lines show impaired origin licensing capacity as shown through reduced episome replication (Stiff et al. 2013 PMID 23516378). Several biallelic Dup (CDT1-ortholog) loss-of-function Drosophila mutants are either embryonically lethal with some mutants showing a block in replication early in S phase, or present with defect in replication in ovaries of adult females (Whittaker et al. 2000 PMID 10898791). In summary, there is definitive evidence to support the relationship between CDT1 and autosomal recessive Meier-Gorlin syndrome 4. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.