Optyczne mapowanie genomu pozwala zidentyfikować klinicznych ważne somatic strukturalne zmiany wariantów w tkance mózgu osób z epilepsją
Optical genome mapping identifies clinically relevant somatic structural variation in epilepsy-affected brain tissue
W skrócie
Badacze użyli nowej techniki optycznego mapowania genomu do badania tkanki mózgu pacjentów z epilepsją i odkryli duże zmiany genetyczne, których zwykłe testy nie potrafią wychwycić. U jednego pacjenta znaleźli somatic wariant (zmianę w komórkach mózgu, a nie dziedziczną) - niewielki brakujący fragment DNA, który potwierdza znaną teorię o dwóch zmianach genetycznych koniecznych do powstania tej choroby. Ta nowa metoda może w przyszłości pomóc w dokładniejszej diagnozie i zrozumieniu epilepsji oraz innych zaburzeń neurologicznych.
Oryginalny abstract (angielski)
Somatic variants are a prominent cause of epilepsy-associated cortical malformations, but about half of patients undergoing genetic testing have no finding due partly to limitations in variant detection. Most studies have focused on single-nucleotide variants or small indels that are accessible to short-read sequencing technologies, but somatic structural variants are also emerging as important contributors despite their unique detection challenges. Optical genome mapping (OGM) is a promising methodology for the detection of structural variants, but requires high quality, high molecular weight DNA from clinical specimens. Here we successfully optimize a protocol for OGM of surgically-resected patient brain tissue which yields ∼450x effective coverage - suitable for detecting somatic variants at low allele fractions. We apply this approach to brain specimens from four patients with epilepsy. OGM identifies large and complex mosaic structural variants ranging from 7-40% variant allele fraction, most of which are not captured by short-read exome sequencing of the same specimen. In one patient with a known germline variant, OGM reveals a somatic variant a 13.2kb deletion in at approximately 20% VAF - consistent with the established two-hit model in DEPDC5-associated lesional epilepsies. By resolving the breakpoints in PacBio HiFi sequencing data, we identify a mechanism for this somatic deletion, mediated by recombination of two Alu elements flanking the region. Our findings demonstrate that OGM is a robust and complementary tool for detecting somatic structural variation in human brain tissue, with potential to improve diagnostic yield and refine genotype-phenotype correlations in neurological disorders.