Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions

Abstract

Purpose: Ellis-van Creveld (EVC) syndrome is an autosomal recessive skeletal ciliopathy that was first identified in the Old Order Amish. Since its discovery, two causal genes have been identified, EVC and EVC2, showing that several cases were misdiagnosed and were, in fact, other entities. Nevertheless, there has not been any adequate phenotypic characterization of molecularly defined EVC syndrome so far.

Methods: We performed a systematic review of case reports of EVC syndrome with molecular confirmation of pathogenic variants in EVC or EVC2. Demographic, genetic, and clinical information of patients was assessed.

Results: We reviewed 725 papers and obtained 54 case reports/series that met the inclusion criteria, with a total subject sample of 310. Of these, 190 had biallelic variants, whereas 28 were affected heterozygotes. Our analysis revealed new phenotypes that have not been classically linked to the syndrome and others that have been linked but are very rare. Monoallelic symptomatic forms had less expressivity, and biallelic cases were milder if associated with EVC and/or missense variants. Finally, we identified CRMP1, a gene whose coding region partially overlaps with EVC, as a potential genetic modifier of the severity of the EVC syndrome.

Conclusion: We provided the first objective clinical characterization of molecularly defined EVC syndrome and identified the first associated genetic modifier, CRMP1, which had not been implicated in human disease before.

Keywords: CRMP1; EVC; EVC2; Ellis-van Creveld; Skeletal ciliopathy.

Figure 1

Flowthrough of the systematic review and collected sample. (A) Flowthrough of the systematic review, with indication of excluding criteria for assessed manuscripts. The sample size refers to the number of published manuscripts. (B) Schematic of the patient sample, with sample size referring to the number of individual cases (independently of being in the same family or not).

Figure 2

Comparison of phenotype frequency between variant types. (A) Plotting of the effect size of the proportion analysis vs the significance value (in a minus logarithm scale) for the association of phenotypes to allelism, (B) mutated gene, and (C) type of variant. The sign of the effect size value represents the direction of the effect. The dashed line represents the cutoff value for a 95% confidence interval. Each dot represents one specific phenotype, with colors relating to the general group in which it is included: blue for skeletal findings, red for heart conditions, green for anthropometric changes, orange for facial features, and gray for other features. EVC, Ellis-van Creveld.

Figure 3

Distribution of phenotype categories between variant types. (A) Radial plot of the frequency of each general phenotype per subtype of variant or (B) general phenotype per gene and variant type. Each radial track represents 20% of proportion, with the outer layer corresponding to 100%. CNV, copy number variant; EVC, Ellis-van Creveld.

Figure 4

Assessment ofCRMP1as a potential modifier of EVC syndrome severity. (A) Schematic representation of the human genome map in the area, including EVC2, EVC, and CRMP1. Arrows indicate transcription direction. Genomic coordinates refer to the GRCh38 version of the human genome. (B) Plotting of the effect size of the proportion analysis vs the significance value (in a minus logarithm scale) for the association of phenotypes to variants affecting EVC only vs EVC and CRMP1. The dashed line represents the cutoff value for a 95% confidence interval. Each dot represents one specific phenotype, with colors relating to the general group in which it is included: blue for skeletal findings, red for heart conditions, green for anthropometric changes, orange for facial features, and gray for other features. EVC, Ellis-van Creveld.