Submission Details

Constitutional human pathogenic variants in the POLD1 gene were first reported in association with autosomal dominant MDPL (Mandibular Hypoplasia, Deafness, Progeroid features, and Lipodystrophy) syndrome in 2013 (Weedon et al., 2013; PMID: 23770608). The syndrome had first been described in 2010 by Shastry et al, in seven unrelated patients diagnosed with an autosomal dominant segmental progeroid syndrome. These cases lacked the pathogenic variants in the known causal genes LMNA or ZMPSTE24 (PMID:20631028). MDPL is characterized by distinctive facial features including dental overcrowding and mandibular hypoplasia, scleroderma-like skin tightening, telangiectasia, and ligament contractures as well as sensorineural hearing loss, subcutaneous fat loss and sequelae such as diabetes, loss of limb muscle mass, and male hypogonadism (PMID:23770608).
We have curated the inheritance pattern for POLD1 - related mandibular hypoplasia-deafness-progeroid syndrome as autosomal dominant, because a dominant mode of inheritance has consistently been reported (PMID: 23770608; Zuo et al., PMID: 36280868). Heterozygous variants, including an in-frame single amino acid deletion in the polymerase domain (c.1812_1814delCTC, p.Ser605del) that accounts for most cases, as well as several different missense variants, have been reported in individuals with MDPL syndrome. Missense variants associated with MDPL include p.Arg506Cys and a cluster of variants in the CysB domain of the protein. Phenotypic expression shows some variability (PMID: 31944473, 26172944). Unlike in MDPL, pathogenic variants in the exonuclease (proofreading) domain of POLE and POLD1 are associated with colorectal and endometrial cancers (PMID: 23263490, 32792570). At least 7 pathogenic variants (primarily de novo, including recurrent in-frame deletion or missense variants) in the POLD1 gene have implicated in MDPL syndrome. These variants have been curated in at least 20 probands in 14 publications (PMIDs: 25131834, 38280868, 34517090, 35590056, 23770608, 29199204, 33369179, 28521875, 26350127, 28791128, 26172944, 33618333, 33863234, 28199729). More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene-disease relationship is supported by loss of polymerase activity in vitro of DNA polymerase delta including POLD1 with the in-frame deletion variant S605del (PMID: 23770608). Total points for the experimental evidence are 1. The total score for genetic and experimental evidence together are 13. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism, and phenotype spectrum for variants causing MDPL syndrome vs. colorectal cancer and T-cell immunodeficiency. Therefore, we curated POLD1 as a split curation for autosomal dominant mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (OMIM: 615381). Autosomal dominant colorectal cancer susceptibility (OMIM: 612591) and autosomal recessive T- cell immunodeficiency (OMIM: 620836) will be curated separately in split curations.
In summary, POLD1 is definitively associated with autosomal dominant mandibular hypoplasia, deafness, progeroid features, and associated lipodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Gene-Disease Validity Standard Operating Procedures (SOP) - SOP11.