Optical genome mapping with genome sequencing identifies subtelomeric Xq28 deletion and inserted 7p22.3 duplication in a male with multisystem developmental disorder.

We report a 17-year-old male with supravalvular stenosis, initial failure to thrive and delayed early development, short stature, acromelia, dysmorphic facial features, hypertelorism, macrocephaly, syringomyelia, hypertension, and anxiety disorder. Fluorescent in situ hybridization (FISH), chromosomal microarray analysis (CMA), and exome sequencing (ES) were nondiagnostic. Combined optical genome mapping (OGM) and genome sequencing (GS) showed a complex rearrangement including an X chromosome with a 22.5 kb deletion in band Xq28 replaced by a 61.4 kb insertion of duplicated chromosome 7p22.3 material. The deletion removes the distal 3' untranslated region (UTR) of FUNDC2, the entire CMC4 and MTCP1, and the first five exons of BRCC3. Transcriptome analysis revealed absent expression of CMC4 and MTCP1 and BRCC3 with normal transcript level of FUNDC2. The inserted duplication includes only one known gene: UNCX. Similar overlapping Xq28 deletions have been reported to be associated with Moyamoya disease (MMD), short stature, hypergonadotropic hypogonadism (HH), and facial dysmorphism. Although he has short stature, our patient does not have signs of Moyamoya arteriopathy or hypogonadism. The structurally abnormal X chromosome was present in his mother, but not in his unaffected brother, maternal uncle, or maternal grandparents. We propose that the combination of his absent Xq28 and duplicated 7p22.3 genomic material is responsible for his phenotype. This case highlights the potential of combined OGM and GS for detecting complex structural variants compared with standard of care genetic testing such as CMA and ES.

Detection of Constitutional Structural Variants by Optical Genome Mapping: A Multisite Study of Postnatal Samples.

Optical genome mapping is a high-resolution technology that can detect all types of structural variations in the genome. This second phase of a multisite study compares the performance of optical genome mapping and current standard-of-care methods for diagnostic testing of individuals with constitutional disorders, including neurodevelopmental impairments and congenital anomalies. Among the 627 analyses in phase 2, 405 were of retrospective samples supplied by five diagnostic centers in the United States and 94 were prospective samples collected over 18 months by two diagnostic centers (June 2021 to October 2022). Additional samples represented a family cohort to determine inheritance (n = 119) and controls (n = 9). Full concordance of results between optical genome mapping and one or more standard-of-care diagnostic tests was 98.6% (618/627), with partial concordance in an additional 1.1% (7/627).