Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders

Abstract

While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing. OGM was performed in 47 families using ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV and copy number variant calling. We identified 7 variants of interest, of which 5 (10.6%) were classified as likely pathogenic or pathogenic, located in BCL11A, OPHN1, PHF8, SON, and NFIA. We also identified an inversion disrupting NAALADL2, a gene which previously was found to harbor complex rearrangements in two NDD cases. Variants in known NDD genes or candidate variants of interest missed by exome sequencing mainly consisted of larger insertions (> 1kbp), inversions, and deletions/duplications of a low number of exons (1-4 exons). In conclusion, in addition to improving molecular diagnosis in NDDs, this technique may also reveal novel NDD genes which may harbor complex SVs often missed by standard sequencing techniques.

Keywords: Copy number variants; Neurodevelopmental disorders; Optical genome mapping; Structural variants; Unsolved cases.

Figure 1

Variant identified via OGM in this study. Reference map: Green; Case map: Blue. (A) In family FIN44, a 19.5 kb intragenic hemizygous duplication in OPHN1 affecting 4 exons was identified as ogm[GRCh38] Xq12 (68205934_68225423) × 2; (B) In family FIN66, a mosaic 27.8 Mb balanced paracentric inversion was found as ogm[GRCh38] inv(1p35.1p31.3)(33246132_61045156). One of the two breakpoints affects the NFIA gene. (C) In family FIN70, we identified a heterozygous 2.4 kb deletion verified to affect the first exon of SON, ogm[GRCh38]21q22.11(33538696_33548254) × 1. (D) In family FIN78, we identified a hemizygous 17.7 kb deletion covering the first two coding exons of PHF8, ogm[GRCh38] Xp11.22(54030836_54059408) × 0. (E) In family FIN105, we identified a heterozygous 2.1 kb deletion ogm[GRCh38] 2p16.1(60458858_60463416) × 1 partially deleting an exon of BCL11A. Molecule support for each variant is presented in Suppl. Fig. 2.