Global developmental delay and intellectual disability associated with a de novo TOP2B mutation

Abstract Background More than 100 genes had been identified for autism spectrum disorder (ASD). With the advancement of whole-exome/genome sequencing (WES/WGS), disease-causing gene in ASD can be identified in a holistic and unbiased approach. The identification of new ASD genes can further explore the molecular basis of ASD. Methods We report a 15 yo girl with developmental delay, intellectual disability, hypotonia, microcephaly and autistic feature. She first presented at 6 months old with primitive response to noise. Physical examination showed the patient was hypotonic despite normal muscle power and reflexes. She also had progressive microcephaly. Developmental assessment at 6 y showed the patient had a corresponding functional age of 1 y. The patient also had autistic feature. Results The patient had no abnormal biochemical or radiological findings. To investigate the molecular basis of the clinical presentation, we applied clinical whole-exome sequencing (WES) for the proband and the family, and we identified a novel de novo heterozygous missense pathogenic variant, TOP2B : NM_001068.2:c.172C > T; NP_001059.2:p.His58Tyr. TOP2B encodes for the enzyme, topoisomerase II isoenzyme beta which is abundant in both developing and adult brain. Defect of topoisomerase is also known to cause ASD. Conclusions Using clinical WES, we were able to identify the disease-causing gene for this patient in a holistic approach and end the diagnostic odyssey with a therapeutic impact.