Welcome to our October edition! This month we continue our Molecular Mechanisms series by showing how AION can prioritize Variants of Uncertain Significance (VUS) for testing with further confirming laboratory methods, helping to establish their pathogenicity. Last month, we covered the power of accurate phenotype description.
In the framework of a project to identify the causative mutations in a cohort of patients affected by multiple diseases, a user submitted a whole exome case affected by neurodevelopmental delay, nystagmus, and a peripheral axonal neuropathy. In this case, a missense variant in KIF1A (p.Leu249Pro, c.746T>C) was prioritized in rank #1, not only due to phenotype matching between the patient and the candidate disease, but also due to AION's Variant Score prediction of pathogenicity (91%). This prediction was driven by a moderate conservation (75%), regional constraint (99%) and a concordant prediction of moderate protein affectation (99%). At the time of the analysis, this variant was not described in ClinVar, and ACMG evaluated this variant as a Variant of Uncertain Significance (VUS).
Despite lack of direct evidence, and given its strong prioritization by AION Variant score and its location in the Kinesin motor domain (where many other pathogenic variants have been found previously) this variant was highlighted in the report, and in consequence, segregation of this variant in the patient’s parents was analysed to gather more molecular evidence of causality. Sanger sequencing revealed that this variant was a de novo variant (absent from the parents), thus confirming its pathogenicity. Interestingly, this variant was later annotated as Likely Pathogenic in ClinVar due to description in other patients. This case illustrates how AION’s machine learning algorithms can perform correct predictions of pathogenicity in cases where the variant has not been previously described in databases!
Variants in the KIF1A (Kinesin Family Member 1A) gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal dominant (de novo) Mental retardation type 9 (Lee et al., 2015; Pennings et al., 2020). This latter, presented by the patient reported here, was very recently renamed as NESCAV (NEurodegeneration and Spasticity with or without Cerebellar Atrophy or Cortical Visual impairment). Interestingly, most mutations in these three diseases map to the Kinesin motor domain. Nevertheless, it is not yet fully understood why some variants cause neurodevelopmental delay, while others result in milder phenotypes not involving the brain. In the same fashion, it is not yet known why some variants cause dominant forms, while others are recessively inherited. A recent study suggested that increased severity is associated with differential location of variants in protein regions involved with ATP and MT binding (Boyle et al., 2021).
Although the variant in our patient was associated to all of these diseases in AION, with different rankings, the disease in rank #1 was correctly prioritized due to its autosomal dominant inheritance and strong phenotypic match with the patient's symptoms.
We'll be back with a new case next month! Want to crack your own cases on AION? Start your free trial now!