Clinical characterization and analysis of the POLE gene in three Chinese patients with IMAGEI syndrome

POLE encodes the catalytic subunit of DNA polymerase ε, and its associated recessive disorders include IMAGEI and FILS syndrome. The purpose of this study is to expand the phenotypes and genotypes of POLE-related IMAGEI syndrome and analyze the phenotypic distribution of POLE-related recessive diseases. We reported the nature courses of three cases with biallelic POLE variants up to 19 years. Exome-sequencing was performed, and alterations in mRNA splicing were determined. PubMed database was electronically searched to collect POLE-related recessive diseases for the literature review. We described three patients from three different families, case 1 and 2 are male and case 3 is female. Three patients presented with intrauterine growth restriction (IUGR), short stature, adrenal insufficiency, epilepsy, and anemia. All patients exhibited compound heterozygous variants in the POLE gene: they shared the same variant c.6747 + 39_6748-47delinsG, and carried 3 other different variants respectively: c.2319 + 65G > A, c.1351 C > T, and c.847dup. The unique deep intronic mutation produced aberrantly spliced mRNAs. As a result of the literature review, the most prominent phenotypes of IMAGEI syndrome include distinctive facial features, IUGR or short stature, genitourinary abnormalities in males, and adrenal insufficiency. In contrast, the key clinical features of FILS syndrome are skin abnormalities, immunodeficiency, characteristic facial features, and IUGR or short stature. This study reports the clinical and molecular characteristics of a Chinese cohort with POLE-related IMAGEI syndrome and learn the top 5 symptoms are IUGR\short stature\adrenal insufficiency\facial features\skin abnormalities by comparison with other POLE-related diseases. The results further expand the phenotypic and genotypic spectrum, enhancing our understanding of POLE-associated recessive syndrome.