Optical genome mapping enables constitutional chromosomal aberration detection.

Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."

A rare homozygous p.Arg87Trp variant of the GBA gene in Gaucher disease: A case report.

Gaucher disease (GD) is a rare metabolic disorder due to pathogenic variants in the GBA gene. We report the first case of the rare p.Arg87Trp pathogenic variant (formerly known as R48W) of the GBA gene in the Tunisian population. A female Arab patient was assessed at the age of 26 due to abdominal distension, bone pain, and headache since she was 25. Physical examination revealed splenomegaly, rib deformation, lumbar scoliosis, and upper limb tremor. Bone marrow was infiltrated by Gaucher cells. The patient was homozygous for the rare p.Arg87Trp variant which is known to be associated with a mild phenotype. This report highlights the necessity of screening the Tunisian population for this rare variant.