Diagnosis of Shashi-Pena Syndrome Caused by Chromosomal Rearrangement Using Nanopore Sequencing

The aim of this study was to uncover the genetic cause of delayed psychomotor development and variable intellectual disability in a proband whose previous genetic analyses, including chromosome microarray and whole exome sequencing, had been negative.

Long-read sequencing Oxford Nanopore Technology and RNA-seq analysis were performed on peripheral blood mononuclear cells. Genes with a fold change ≥ 1.5 and p ≤ 0.05 were identified as differentially expressed.

Clinical examinations showed that the proband's features were similar to a rare autosomal-dominant neurodevelopmental syndrome, Shashi-Pena syndrome (MIM #617190). Karyotyping showed that a chromosomal balanced translocation t(2; 11) (p23; q23) was detected in the proband, her father, and her grandmother. Meanwhile, long-read sequencing identified 102 balanced translocations and 145 inversions affecting ASXL2 at an average of 15×. Combined with the family's RNA-seq results, the average mRNA expression of ASXL2 decreased in the patients.

We identified a complex chromosomal rearrangement affecting ASXL2 as a pathogenic mechanism of Shashi-Pena syndrome in a Chinese family. This case study suggests that nanopore sequencing is suitable for pathogenic analysis of complex rearrangements, providing new avenues for the diagnosis of genetic diseases.