Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder
Francesca Mattioli, Hossein Darvish, Sohail Aziz Paracha, Abbas Tafakhori, Saghar Ghasemi Firouzabadi, Marjan Chapi, Hafiz Muhammad Azhar Baig, Alexandre Reymond, Stylianos E. Antonarakis, Muhammad Ansar
Abstract
Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.