From cue to meaning: The involvement of POLD1 gene in DNA replication, repair and aging

Murdocca, Michela; Spitalieri, Paola; D’Apice, Maria Rosaria; Novelli, Giuseppe; Sangiuolo, Federica

doi:10.1016/j.mad.2023.111790

Cited by 3 publications

(1 citation statement)

References 80 publications

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“…None of the patients tested with the congenital disorders herein mentioned show complete lack of POLE expression, suggesting that this would be lethal to the embryo. Constitutional heterozygous POLD1 pathogenic variants that impair the polymerase (replicative) activity of Polδ (dominant negative effect), cause an autosomal dominant progeroid syndrome called MDPL (MIM# 615381), characterized by mandibular hypoplasia, deafness, progeroid features, and lipodystrophy [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

Mur,

Viana-Errasti,

García-Mulero

et al. 2023

Genome Med

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Background Germline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases. Methods A training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered. Results Gene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign. Conclusions Our recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.

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Section: Introductionmentioning

confidence: 99%

Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

Mur,

Viana-Errasti,

García-Mulero

et al. 2023

Genome Med

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New frontiers in ageing and longevity: Sex and gender medicine

Balistreri

2023

Mechanisms of Ageing and Development

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Anesthetic management of a patient with mandibular hypoplasia, deafness, progeroid features, lipodystrophy syndrome: a case report

Sekiguchi,

Kinoshita,

Sakai

et al. 2024

JA Clin Rep

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Background Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder that presents unique challenges for anesthetic management due to its multisystemic manifestations. This report outlines the anesthetic considerations for MDPL patients based on our case experience. Case presentation A 15-year-old male with MDPL syndrome underwent testicular extraction under general anesthesia. Insertion of a peripheral venous catheter was challenging due to scleroderma-like skin. Although the facial features of MDPL syndrome suggested a difficult airway, intubation with a McGrath™ Mac video laryngoscope was successful. Despite MDPL syndrome’s association with hypertriglyceridemia due to lipodystrophy, this patient’s triglyceride levels were normal. Thiamylal and sevoflurane were used without issues such as delayed emergence from anesthesia. Conclusions MDPL syndrome requires careful preoperative assessment and tailored anesthetic management due to potential airway challenges arising from its distinctive facial features and the possibility of altered anesthetic pharmacokinetics associated with lipodystrophy.

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From cue to meaning: The involvement of POLD1 gene in DNA replication, repair and aging

Cited by 3 publications

References 80 publications

Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

New frontiers in ageing and longevity: Sex and gender medicine

Anesthetic management of a patient with mandibular hypoplasia, deafness, progeroid features, lipodystrophy syndrome: a case report

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