Author: Edgard Verdura, PhD
This month marks the kick-off of a series in which we’re featuring some interesting cases that serve as a great example of how AION can improve your diagnostic process when standard databases or ACMG guidelines don’t have the answer. In our first example, a geneticist from the genetics department of an Austrian university uploaded a case of a female child (<10 years old) through AION and kindly agreed to feature this case on the blog. The case presented tonic-clonic seizures and developmental delay among other symptoms.
Initial genetic screening did not offer any hints on the diagnosis, so the case was sequenced by Whole Exome Sequencing (WES). The corresponding VCF file was submitted to the AION platform together with a curated list of patient HPOs.
Through phenotype-based prioritization, our pipeline ranked the PCDH19 missense variant p.Cys330Phe (c.989G>T, exon 1) in the top 1 rank. Interestingly, this variant was not described in ClinVar at the time of the analysis, and ACMG criteria evaluated this variant as a VUS (a variant of unknown significance). However, our Nostos Genomics in-house ML score evaluated this variant to be Pathogenic with 96% confidence. This prediction was fuelled by regional constraints in the region where this variant is located (Moderate, 99% confidence), missense pathogenicity predictors (Moderate, 99% confidence), and finally, by a significant amino acid conservation (High, 99% confidence). This variant was also absent from control databases. After segregation studies and clinical evaluation, the variant was found to be highly concordant with the phenotype and thus was evaluated as causative.
Thus, our machine learning model pinpointed a candidate variant that was not described in databases nor prioritized by ACMG guidelines. This illustrates how AION can help diagnose cases harboring variants of unknown significance.
Up to now, PCDH19 and EFNB1 are the only two genes associated with a particularly rare mode of inheritance, X-linked cellular interference, theoretically specific to genes in the X chromosome presumably coding for proteins in the cell membrane. The underlying pathogenic mechanism, cellular interference, arises from the existence of two different subpopulations of cells in the same patient: one expressing the wild-type allele, and the other expressing the mutated allele [Gross 2018]. In this mode of inheritance, only heterozygous female patients (and some rarely described mosaic males) are affected, while in contrast, hemizygous males are spared [Depienne et al., 2009]. This is in opposition to most X-linked diseases, which typically exhibit more severe phenotypes in males than females.Thus, the AION platform took advantage of accurate, updated database information on modes of inheritance to prioritize a variant in a gene with a very particular mode of inheritance.
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In AION, we have prepared some trial cases for you to analyze. You can also upload your own cases!
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