Phenotypic continuum between POLE‐related recessive disorders: A case report and literature review
- 21 July 2022
- journal article
- review article
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 188 (10) , 3121-3125
Abstract
POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading‐associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss‐of‐function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE‐related recessive disorders.Keywords
This publication has 11 references indexed in Scilit:
- Role of POLE and POLD1 in familial cancerGenetics in Medicine, 2020
- DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable ImmunodeficiencyThe American Journal of Human Genetics, 2018
- Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencingGenetics in Medicine, 2018
- A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromesBMC Medical Genetics, 2015
- Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomasInternational Journal of Cancer, 2014
- DNA polymerase ε and its roles in genome stabilityIUBMB Life, 2014
- Polymerase Proofreading-Associated PolyposisDiseases of the Colon & Rectum, 2014
- Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomasNature Genetics, 2012
- Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”)Journal of Experimental Medicine, 2012
- Mouse models of DNA polymerasesEnvironmental and Molecular Mutagenesis, 2012