Long-Read Sequencing of a Neurodevelopmental Disorder Patient Reveals Complex Rearrangement Involving the ARID1B Gene

Long-read sequencing can identify disease-causing variants that are missed by short-read sequencing. Here, we report the use of Oxford Nanopore Technology long-read sequencing to resolve a complex translocation-inversion involving the ARID1B gene in a 5-year-old male with a history of febrile seizures, intractable epilepsy, epileptic encephalopathy, and speech delay. Prior clinical genetic testing included a karyotype with a t(6;11)(q25.3;q22.3) apparently balanced translocation and a chromosomal microarray with a 1.48 Mb interstitial deletion within 4p13 that were both deemed not clinically significant, normal fragile X and Prader-Willi/Angelman DNA assays, and no significant findings on epilepsy or neurotransmitter disorders gene panels. Extensive metabolic testing was also negative. The patient was enrolled in the University of North Carolina (UNC) Genetic Determinants of Neurological and Developmental Disorders (GDNDD) study. Research short-read genome single nucleotide and structural variant analysis was negative. Subsequent identification by long-read sequencing that the translocation interrupted the ARID1B gene highlights the use of long-read sequencing to identify and resolve complex rearrangements underlying genetic disorders and may be valuable in determining the pathogenicity of unexplained balanced translocations for other genetic disorders.