Long-read sequencing and optical genome mapping identify causative gene disruptions in noncoding sequence in two patients with neurologic disease and known chromosome abnormalities.

Autor: Sund KL; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Liu J; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA., Lee J; Bionano Genomics, San Diego, California, USA., Garbe J; University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA., Abdelhamed Z; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Maag C; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Hallinan B; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.; Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Wu SW; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.; Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Sperry E; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Deshpande A; University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA., Stottmann R; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA., Smolarek TA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA., Dyer LM; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA., Hestand MS; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Jul 23, pp. e63818. Date of Electronic Publication: 2024 Jul 23.
DOI: 10.1002/ajmg.a.63818
Abstrakt: Despite advances in next generation sequencing (NGS), genetic diagnoses remain elusive for many patients with neurologic syndromes. Long-read sequencing (LRS) and optical genome mapping (OGM) technologies improve upon existing capabilities in the detection and interpretation of structural variation in repetitive DNA, on a single haplotype, while also providing enhanced breakpoint resolution. We performed LRS and OGM on two patients with known chromosomal rearrangements and inconclusive Sanger or NGS. The first patient, who had epilepsy and developmental delay, had a complex translocation between two chromosomes that included insertion and inversion events. The second patient, who had a movement disorder, had an inversion on a single chromosome disrupted by multiple smaller inversions and insertions. Sequence level resolution of the rearrangements identified pathogenic breaks in noncoding sequence in or near known disease-causing genes with relevant neurologic phenotypes (MBD5, NKX2-1). These specific variants have not been reported previously, but expected molecular consequences are consistent with previously reported cases. As the use of LRS and OGM technologies for clinical testing increases and data analyses become more standardized, these methods along with multiomic data to validate noncoding variation effects will improve diagnostic yield and increase the proportion of probands with detectable pathogenic variants for known genes implicated in neurogenetic disease.
(© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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