PT - JOURNAL ARTICLE AU - Guido Vogt AU - Sarah Verheyen AU - Sarina Schwartzmann AU - Nadja Ehmke AU - Cornelia Potratz AU - Anette Schwerin-Nagel AU - Barbara Plecko AU - Manuel Holtgrewe AU - Dominik Seelow AU - Jasmin Blatterer AU - Michael R Speicher AU - Uwe Kornak AU - Denise Horn AU - Stefan Mundlos AU - Björn Fischer-Zirnsak AU - Felix Boschann TI - Biallelic truncating variants in <em>ATP9A</em> cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive AID - 10.1136/jmedgenet-2021-107843 DP - 2021 Jun 18 TA - Journal of Medical Genetics PG - jmedgenet-2021-107843 4099 - http://jmg.bmj.com/content/early/2021/06/17/jmedgenet-2021-107843.short 4100 - http://jmg.bmj.com/content/early/2021/06/17/jmedgenet-2021-107843.full AB - Background Genes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM).Methods Exome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants.Results We detected homozygous truncating variants in ATP9A. While the variant in family A is predicted to result in an early premature termination codon, the variant in family B affects a canonical splice site. Both variants lead to a substantial reduction of ATP9A mRNA expression. It has been shown previously that ATP9A localises to early and recycling endosomes, whereas its depletion leads to altered gene expression of components from this compartment. Consistent with previous findings, we also observed overexpression of ARPC3 and SNX3, genes strongly interacting with ATP9A.Conclusion In aggregate, our findings show that pathogenic variants in ATP9A cause a novel autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, our results underline a crucial role of this gene in endosomal transport in brain tissue.All data relevant to the study are included in the article or uploaded as supplementary information. For further information, contact the corresponding author (felix.boschann@charite.de).