Genotype-phenotype correlation in pseudoxanthoma elasticum

Abstract

Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.

Phenotypic Features and Genetic Findings in a Cohort of Italian Pseudoxanthoma Elasticum Patients and Update of the Ophthalmologic Evaluation Score

“…These data further underline the complexity of the PXE genotype, as rare sequence variants in other genes can also contribute to the pathogenesis of the disease [ 30 , 48 , 61 ], and/or additional polymorphisms can modulate the onset, the progression and the severity of the disease [ 27 , 48 , 61 , 62 ]. Bartstra and coworkers recently described a correlation between the type of variants and specific parameters as calcification mass score and choroidal neovascularization in PXE [ 63 ]. This discrepancy is due to the different parameters used to correlate the type of sequence variants, as we have adopted the Phenodex index which, being mainly based on clinical evaluations, has been widely used in the routine clinical practice to easily reflect the global severity of the disease [ 21 , 22 ].…”

Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks

“…The exact risk for cardiovascular system involvement in PXE remains unknown [2]. However, in an analysis of genotype-phenotype correlations in 289 patients with PXE, biallelic truncating variants were associated with more severe arterial and ophthalmological phenotypes than those of patients with mixed genotypes of one truncating and one non-truncating variant [3]. Additionally, severe skin phenotypes are correlated with cardiovascular and ophthalmic phenotypes [25,26].…”

“…Angioid streaks (AS) are breaks in the Bruch's membrane radiating from the optic disc [1][2][3]. AS area hallmark of pseudoxanthoma elasticum (PXE; OMIM #264800), and of various systemic conditions such as Paget's disease of bone and sickle-cell anemia [4].…”

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

“…The lack of genotype/phenotype correlation only compounds the problem. However, a very recent clinical study performed with 289 PXE patients found that mixed genotype led to less severe arterial calcification and ocular manifestations than patients with two truncating ABCC6 variants and suggested that environmental or modifier genes could also contribute to the still unexplained phenotypic variability in PXE [ 153 ]. The presence of modifier genes modulating calcification in PXE has been investigated in human and mice but their predictive values for clinical applications are not clear [ 109 , 110 , 147 , 150 , 154 , 155 , 156 ].…”