2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-RNA-sequencing positional gene enrichment is a useful tool in resolving cases of X chromosome copy number variation

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Researchers at the University of Utah have demonstrated the usefulness of RNA-sequencing positional gene enrichment in resolving cases of X chromosome copy number variation (CNV). CNVs on the X chromosome have been associated with various phenotypes, and the severity of these phenotypes often depends on the size and location of the CNV. In males with a single X chromosome, the effects are typically more severe than in females, although skewed X chromosome inactivation (XCI) can modify the phenotype in females.<br /><br />While XCI analysis can reveal if XCI is skewed, it cannot determine which chromosome is being preferentially inactivated. RNA-sequencing, on the other hand, can assess differential gene expression by comparing transcript abundance in a sample to controls. This allows for the mapping of differentially expressed genes to their exact location on the chromosome. In a case study, RNA-sequencing was used to investigate an affected female with an Xq22.1 to Xq28 duplication and an Xq28 triplication. The RNA-sequencing analysis revealed atypical XCI skewing, suggesting that the chromosomal aberration was likely pathogenic.<br /><br />The patient in this study was a 6-year-old female with multiple congenital anomalies, including hydrocephalus, underdeveloped extremities, and intellectual disability. She had a highly skewed XCI pattern in peripheral blood and a moderately skewed pattern in fibroblasts. Positional analysis of upregulated genes identified an enrichment of X chromosome genes between the Xq22.1 and Xq28 regions. By comparing this patient to other females with Xq copy number gains, the researchers associated specific genes such as ALG13, HNRNPH2, NAA10, NSDHL, and DKC1 with the phenotypes observed in the patient.<br /><br />By combining routine cytogenetic and molecular testing with differential expression and positional gene enrichment analyses using RNA-sequencing, researchers can effectively resolve the effects of chromosomal CNVs, particularly in individuals with suspected pathogenic XCI skewing. This approach provides valuable insights into the relationship between gene expression and phenotype in patients with X chromosome variations.

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Presenting Author - Robert G. Lewis, PhD; Co-Author - David H. Viskochil, MD, PhD; Co-Author - Ashley Andrews, MSN, CPNP; Co-Author - Karin M. Dent, MS, CGC; Co-Author - Rong Mao, MD; Co-Author - Lorenzo D. Botto, MD, FACMG; Co-Author - Pinar Bayrak-Toydemir;

Meta Tag

Bioinformatics

Chromosomal Abnormalities

Chromosome Structure/Function

Clinical Applications of Molecular Cytogenetics

Clinical Cytogenetics

Cytogenetics

Genetic Testing

Genome sequencing

Intellectual disability

NextGen Sequencing

Sequencing

X-Inactivation/X-Linked Disease

Co-Author David H. Viskochil, MD, PhD

Co-Author Ashley Andrews, MSN, CPNP

Co-Author Karin M. Dent, MS, CGC

Co-Author Rong Mao, MD

Co-Author Lorenzo D. Botto, MD, FACMG

Co-Author Pinar Bayrak-Toydemir

Presenting Author Robert G. Lewis, PhD

Keywords

RNA-sequencing

positional gene enrichment

X chromosome copy number variation

CNV

phenotypes

skewed X chromosome inactivation

differential gene expression

chromosomal aberration

congenital anomalies

gene expression and phenotype