Approximately 2–5% of children are born with congenital abnormalities that manifest into more severe neurodevelopmental problems as they age.1 Neurodevelopmental disorders encompass a wide range of severity and behavioral differences, many of which arise from de novo mutations in critical genes during early brain development.2, 3 Exome sequencing has been an effective means of diagnosing patients with similar neurodevelopmental disorders. The molecular diagnosis can be a way to shift from a more phenotype-driven management of the symptoms to a more refined treatment based on genotype.4

Exome sequencing was performed for the patient and his unaffected parents (trio), for which the parents gave written informed consent. Prior to exome sequencing, conventional cytogenetic and molecular analyzes were performed and showed normal results (Supplementary Table 1). After applying standard filtering criteria (de novo exonic or splicing mutation, frequency in ExAC or 1000 genomes <0.01, quality index >50, <4 times found in ‘in-house’ exomes and high CADD score >15) (Supplementary Figure 2), we identified four gene candidates, RHOU, STAT2, CSNK2A1 and PDGFR L. However, only two mutations were confirmed to be real and de novo: STAT2 p.R807G, CSNK2A1 p.D156H (Supplementary Table 2). STAT2 is involved in mitochondrial neurological deterioration, but with a lower CADD score compared to CSNK2A1 and CSNK2A1 have recently been linked to a rare neurodevelopmental disorder and was predicted to be the most damaging change, CADD score 28.6 (Supplementary Table 2).2, 5Specifically, 13 patients with neurodevelopmental disorders and de novo CSNK2A1 mutations have been reported and variations within this gene are associated with developmental disorders at the genome-wide level.2, 5 The de novo mutation in our patient was confirmed by Sanger sequencing. CSNK2A1 p.D156H is located in the active site of protein and the aspartate residue at position 156 is also highly conserved. (GERP score 5.12; Figure 1c and d).

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