Dataset Information

Two rare PROX1 variants in patients with lymphedema.

ABSTRACT: BACKGROUND:The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas. METHODS:We used next-generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease-causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients' genotypes and explore the role of the candidate gene PROX1 in lymphedema. RESULTS:Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants-p.(Leu590His) and p.(Gly106Asp)-indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects. CONCLUSIONS:Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema.

SUBMITTER: Ricci M

PROVIDER: S-EPMC7549596 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Two rare PROX1 variants in patients with lymphedema.

Ricci Maurizio M Amato Bruno B Barati Shila S Compagna Rita R Veselenyiova Dominika D Kenanoglu Sercan S Stuppia Liborio L Beccari Tommaso T Baglivo Mirko M Kurti Danjela D Krajcovic Juraj J Serrani Roberta R Dundar Munis M Basha Syed H SH Chiurazzi Pietro P Bertelli Matteo M

Molecular genetics & genomic medicine 20200805 10

<h4>Background</h4>The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas.<h4>Methods</h4>We used next-generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease-causing genes: 235 of 24 ...[more]

PMID: 32757260

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Project description:Abstract Objectives: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity along with clinical manifestations varying from seizures to frequent fractures. Diagnosis of HPP is complicated both by its variable clinical phenotype and variable age of onset - patients are often asymptomatic well into adulthood. Although caused by variants in the ALPL gene, individual mutations are not tightly correlated with disease due to variable penetrance, expressivity, and the effect of modifier genes. In this study we sought to better understand the genotype/phenotype correlation in HPP by closely examining the clinical courses of a series of 37 patients with two rare variants in ALPL. Methods: Using BioVU, a DNA biobank that pairs patient’s genetic information with their de-identified medical record, we identified all patients that had at least one variant in ALPL. Among these patients, we chose to further study those with one of two variants. One (rs121918002) has previously been associated with disease while the other (rs148405563) was previously reported as benign. Clinical phenotypes and AlkP values were then obtained through manual review of the de-identified medical records of patients with one of these variants. Results: 20 patients with the rs121918002 (disease-associated) and 17 with the rs148405563 (benign) variant had sufficient clinical data for further analysis. None of these patients carried the diagnosis of HPP. Patients with the disease-associated variant had an average serum AlkP activity of 70.67 IU/L (SD 52.22), and 16 patients (80%) had at least one serum AlkP less than the lower limit of normal (40 IU/L). Among patients with a low AlkP, only 6 (30%) had clinical phenotypes consistent with disease. Patients with the benign variant had an average serum AlkP of 53.92 IU/L (SD 16.30) and 8 (47.1%) had at least one serum AlkP less than 40 IU/L. Among those with a low AlkP, 4 patients (23%) also had clinical phenotypes consistent with disease. Conclusions: Our study highlights the importance of clinical context to guide decisions around genetic testing in this population. In particular, genetic testing is of limited utility in those who meet clinical criteria for diagnosis. However, ALPL sequencing may be useful in younger patients with low AlkP but who do not have clinical disease. In these patients it may identify those at highest risk to go on to develop disease and assist in earlier intervention with appropriate therapy.

Project description:PurposeGenetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort.MethodsGenetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses.ResultsWe found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error.ConclusionThe results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene.

Dataset Information

Two rare PROX1 variants in patients with lymphedema.

Publications

Two rare PROX1 variants in patients with lymphedema.

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