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eP428: Gender and sex discordance in genetic testing: Mayo Clinic Genomics Laboratory experience

2022; Elsevier BV; Volume: 24; Issue: 3 Linguagem: Inglês

10.1016/j.gim.2022.01.462

1530-0366

Lauren A. Choate, Kyle Salsbery, Katrina E. Kotzer, Anna Essendrup, Kandelaria M. Rumilla, Nicole J. Boczek, Linda Hasadsri, Hutton M. Kearney, Chen Wang, Ann M. Moyer, Linnea M. Baudhuin, Zhiyv Niu,

BRCA gene mutations in cancer

A patient's sex chromosome complement plays an important role in clinical genetic testing, analysis, and reporting. However, there are inconsistencies and deficiencies in the documentation of gender and sex in many laboratory information systems. Gender is a cultural construct referring to one's deeply felt sense of identity as male, female, or not fitting within either binary category. Whereas sex is a biological construct referring to multiple characteristics, including sex chromosome complement, external anatomy, and hormone production/level and response (phenotype). Many clinical genetic assays target genes and/or control regions on the sex chromosomes. Patient care may be adversely affected when our existing laboratory information systems (LIS) cannot appropriately document or communicate both a patient's gender identity and their sex. For example, a discordance between sex submitted to the laboratory information system and sex chromosome complement determined by the assay may cause concern for a sample mix-up. In other cases, the sex reported in the laboratory information system is factored into the analysis pipeline and determines how sequence or copy number variants are normalized, called, and classified on sex chromosomes. Here we describe two case examples to highlight impacts on next generation sequencing (NGS) analysis and reporting due to this LIS limitation, and approaches used to begin to improve patient care. The first case was resolved prior to reporting, whereas the second case was discovered after reporting and was resolved via a revised report. In the first case, a peripheral neuropathy sequencing panel was ordered for a patient whose sex was reported as female in the laboratory information system. The analytical pipeline identified a GLA gene deletion and additional genetic variants on the X chromosome were called homozygous. As this pattern suggested one X chromosome, a genetic counselor contacted the referring office and eventually confirmed that this patient was assigned male at birth. Once the analytical pipeline was rerun with XY as input, there were no diagnostic findings on the X chromosome. In the second case, an Ehlers-Danlos Syndrome sequencing panel was ordered for a patient with sex reported as female in the laboratory information system. Whole gene deletions of ATP7A and FLNA gene (both present on the X chromosome) were detected and reported with recommendation to consider microarray to characterize possible chromosomal deletions. After reporting, the ordering physician confirmed that the patient was assigned as male at birth. An amended report was issued to address this information and clarify that the single copies of ATP7A and FLNA detected were consistent with an XY chromosomal sex complement. In both cases, the testing lab and ordering office took actions to ensure quality testing and reporting. However, delayed turnaround time, repeat testing, patient counseling, and additional patient stress are all factors that may be impacted when sex/gender discordance such as these occur. Laboratory and electronic medical record systems that are unable to record both a patient's gender and sex have the potential to adversely affect patient outcomes. In genetic assays, the sex listed by the provider is used to analyze variants and may result in false calls for homozygosity and gene deletions or skipping the analysis of whole chromosomes. When discordance is identified between provided sex and chromosomal sex during laboratory testing, additional work is required on both the laboratory and clinical sides leading to increased costs associated with repeat testing and increased turnaround times. When discordance is not identified, an erroneous result and unnecessary follow-up tests may be performed. In both scenarios, this discordance may have a negative emotional impact and lead to additional stress in patients.