Nanopore long-read sequencing analysis reveals ZIC1 dysregulation caused by a de novo 3q inversion with a breakpoint located 7 kb downstream of ZIC1

Zic family member 1 ( ZIC1 ), a gene located on chromosome 3q24, encodes a transcription factor with zinc finger domains that is essential for the normal development of the cerebellum. Heterozygous loss-of-function of ZIC1 causes Dandy-Walker malformation, while heterozygous gain-of-function leads to a multiple congenital anomaly syndrome characterized by craniosynostosis, brain abnormalities, facial features, and learning disability. In this study, we present the results of genetic analysis of a male patient with clinically suspected Gomez-Lopez-Hernandez syndrome. The patient displayed multiple congenital abnormalities, including bicoronal craniosynostosis, characteristic facial features, cerebellar malformation with rhombencephalosynapsis, and temporal alopecia, and a de novo inversion of chromosome 3q. Breakpoint analysis using a Nanopore long-read sequencer revealed a breakpoint in the distal centromere of 3q24 located 7 kb downstream of the 3′ untranslated region of ZIC1 . On the basis of the clinical similarities, we concluded that the abnormalities in this patient were caused by the transcriptional dysregulation of ZIC1 . We hypothesize the underlying molecular mechanisms of transcriptional dysregulation of ZIC1 such as the abnormalities in topologically associated domains encompassing ZIC1 . This study highlights the usefulness of long-read sequencing in the analysis of de novo balanced chromosomal abnormalities.