Global developmental delay and intellectual disability associated with a de novo TOP2B mutation.
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 15yo girl with developmental delay, intellectual disability, hypotonia, microcephaly and autistic feature. She first presented at 6months 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 6y showed the patient had a corresponding functional age of 1y. 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.
Department of Pathology, The University of Hong Kong, Hong Kong, China. Electronic address: ching-wanlam@pathology.hku.hk.
Ching-Wan
CW
Lam
Department of Paediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China.
Wai-Lan
WL
Yeung
Department of Pathology, The University of Hong Kong, Hong Kong, China.
Chun-Yiu
CY
Law
D000293:Adolescent; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D002658:Developmental Disabilities / Q000150:complications* / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000150:complications*; D009154:Mutation; D000073359:Exome Sequencing
D004250:DNA Topoisomerases, Type II
E3 ubiquitin ligase; TOP2B; Topoisomerase; UBE3a; Whole-exome sequencing (WES)