Identification of an NF1 Microdeletion with Optical Genome Mapping

Abstract

Neurofibromatosis type 1 (NF1) is a clinically heterogeneous neurocutaneous disorder inherited in autosomal dominant manner. Approximately 5-10% of the cases are caused by NF1 microdeletions involving the NF1 gene and its flanking regions. Microdeletions, which lead to more severe clinical manifestations, can be subclassified into four different types (type 1, 2, 3 and atypical) according to their size, the genomic location of the breakpoints and the number of genes included within the deletion. Besides the prominent hallmarks of NF1, patients with NF1 microdeletions frequently exhibit specific additional clinical manifestations like dysmorphic facial features, macrocephaly, overgrowth, global developmental delay, cognitive disability and an increased risk of malignancies. It is important to identify the genes co-deleted with NF1, because they are likely to have an effect on the clinical manifestation. Multiplex ligation-dependent probe amplification (MLPA) and microarray analysis are the primary techniques for the investigation of NF1 microdeletions. However, based on previous research, optical genome mapping (OGM) could also serve as an alternative method to identify copy number variations (CNVs). Here, we present a case with NF1 microdeletion identified by means of OGM and demonstrate that this novel technology is a suitable tool for the identification and classification of the NF1 microdeletions.

Keywords: NF1 gene; NF1 microdeletion; OGM; copy number variation; optical genome mapping; structural variation.

Figure 1

Genome map view and whole genome circos plot. Right panel: The whole genome circos plot with a copy number loss visible and highlighted with a red boxed area on the circus plot around the inner circle of the CNV track of chromosome 17. Left panel: The genome map view of the interstitial deletion of 17q11.2 region highlighted in the CNV track and the structural variation (SV) track. Green horizontal bar displays the reference genome with the OGM labels marked with blue vertical lines. Blue horizontal line with small vertical lines demonstrates our sample genome map with labels.

Figure 2

Probe localization on the 17q11.2 microdeletion region. The affected genes and NF1-REP regions in red boxes are displayed schematically at the top of the figure. Vertical blue lines on the green bar show the OGM labels. Orange arrows depicts the NF1 area MLPA probe positions. OGM probes are capable of differentiating between the different types of NF1 microdeletions.