POLD1

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: ClinGen

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.

Inheritance Pattern: AR

Disease ID:MONDO:0970994

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0012953

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014157

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0012953

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012953

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018653

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0970994

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100351

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014157

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0800145

Submitter: ClinGen

POLD1 was first reported in relation to an autosomal recessive non-severe combined immunodeficiency due to polymerase delta deficiency in 2019 (Conde, et al., 2019, PMID:31449058). Of note, this gene has also been implicated in autosomal dominant POLD1-related polyposis and colorectal cancer syndrome and autosomal dominant mandibular hypoplasia-deafness-progeroid syndrome. These have been assessed separately. To date, there are three probands, two homozygous individual and one compound heterozygous individual, reported with biallelic POLD1 missense variants and non-severe combined immunodeficiency due to polymerase delta deficiency. Probands displayed phenotypes including recurrent infections, decreased CD4+ T cells, and T cell lymphocytopenia. Patient P1 from Cui et al. presented with T cells showing defective S phase DNA replication and restrictive V-J gene recombinations. Heterozygous carriers are not known to be affected. This gene-disease association is also supported by one animal model (PMID:19145245). Homozygous POLD1 knock out mice were embryonic lethal by E7.5 with an apparent deficiency in cellular proliferation and DNA replication. The gene-disease association is also supported by biochemical function showing that POLD1 is the catalytic component of DNA polymerase delta, which is a critical enzyme to both DNA replication and DNA repair. Additionally, the gene-disease relationship is supported by rescue, in which transfection of WT-POLD1 was able to restore a deficiency in DNA replication seen in patient cells. Finally, a co-IP assay has shown that POLD1 co-immunoprecipitates with POLD2, which serves as the scaffolding for DNA polymerase delta and has also been implicated in non-severe combined immunodeficiency due to polymerase delta deficiency. In summary, this curation reaches a classification of Limited due to the small number of published patients. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the SCID-CID GCEP on February 16, 2023. It was reevaluated on February 16, 2026. As a result of this reevaluation, the classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0100351

Submitter: ClinGen

The *POLD1* gene encodes the catalytic and proofreading subunit of DNA polymerase-delta, which is responsible for DNA replication and repair. POLD1 was first reported as part of an autosomal dominant cancer susceptibility condition in 2013 (Palles et al, PMID: 23263490). Likely pathogenic/ pathogenic variants located within the region of the gene that encodes the exonuclease domain of POLD1 are associated with an increased risk of colon polyps and colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern and phenotypic variability between susceptibility to colon cancer and colon polyps. Therefore, the following disease entities have been lumped into POLD1-related polyposis and colorectal cancer syndrome (MONDO:0100351). However, due to the phenotypic difference and different molecular mechanism of the pathogenic variants autosomal dominant mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) OMIM 615381 - has been split from this curation. With regard to evidence, 9 missense variants that have been reported in three publications (PMIDs: 26133394, 25559809, 33948826) are included in this curation (10 points). This gene-disease association is also supported by experimental evidence (2.5 points) including mouse, yeast and cell culture models (PMIDs: 19966286, 26087769, 12429860, 19805137). Cells with specific POLD1 variants mirroring those found in humans demonstrated low-fidelity DNA synthesis, leading to increased DNA damage. Pold1 mutant (D400A/D400A) mice also had increased spontaneous mutation rates and developed cancers. In summary, POLD1 is definitively associated with autosomal dominant POLD1-related polyposis and colorectal cancer syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Colon Cancer Expert Panel on 04/10/2017. The ClinGen Hereditary Cancer GCEP reevaluated on 02/24/2023 (SOP Version 9). As a result of this reevaluation, the classification did not change although the disease name was changed to mirror both features of the disorder.