Herkert, J. C. | bioRxiv Science

bioRxiv2022

Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn-/- mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. Increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KRD in the broader group of mTORC1 related disorders affecting brain structure, cognitive function, and network integrity.

genetics↗

bioRxiv2018

Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis

Clinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patients phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 patients without genetic diagnosis, yielded new candidate genes for seven cases. Our results highlight the added value of GADO (www.genenetwork.nl) for increasing diagnostic yield and for implicating previously unknown disease-causing genes.

genetics↗