P801: Low-level somatic convoluted indel variants in C-terminal region of TEK revealed by deep sequencing on patients with vascular malformations

Treatment and Management: For the first patient with the premutation, variable methylation patterns across different tissues make it challenging to assess the risk for fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND).Outcome and Follow-Up: For the second patient, the diagnosis of mosaic Turner syndrome might explain her premature ovarian insufficiency, and the presence of the FMR1 full variant complicates any potential efforts for assisted pregnancy.Discussion: In the first patient, despite the varying methylation patterns across tissues, the premutation peaking at 86 repeats puts her in the highest risk group for an early onset of premature ovarian insufficiency, potentially leading to elevated FSH levels and endometrioma formation.For the second patient, the mosaic X chromosome loss is likely due to instability associated with the FMR1 full variant.Variable levels of X chromosome loss in different tissues might account for the absence of many typical Turner syndrome phenotypes.Conclusion: Caution should be exercised when interpreting methylation results from commonly tested tissues, as affected organs may display different methylation patterns.Karyotyping should be considered for females with the FMR1 full variant, particularly in patients with unexplained features associated with Turner syndrome.Introduction: Fragile X syndrome is more prevalent in males than in females; however, more females carry the FMR1 premutation, whose phenotypic development may be influenced by X-inactivation patterns.In addition, females with FMR1 full variant are at increased risk for the loss of the X chromosome containing the variant.Therefore, appropriate follow-up tests, such as methylation analysis for females with the premutation and karyotyping for females with the full variant, should be considered.Case Presentation: The first patient is a 34-year-old female whose son was diagnosed with fragile X syndrome.She had an ovary removed at age 20 due to an endometrioma and is scheduled for a hysterectomy and potential removal of the remaining ovary due to multiple ovarian cysts.The second patient is a 28-yearold female with normal height, unstable menstruation, and no significant family history.She consulted an OB/GYN due to secondary amenorrhea.Diagnostic Workup: The first patient was tested for FMR1 CGG repeat expansion and found to have premutation CGG repeats (range 80-100, peaking at 86), along with a normal 30 CGG repeats allele in her peripheral blood sample.Follow-up methylation studies revealed that the premutation allele was largely unmethylated with a mosaic methylation pattern (low-level partially methylated for 80-84 repeats, unmethylated for 85-100 repeats), suggesting it is mostly active for transcription.Conversely, the 30 repeats allele was abnormally fully methylated, implying transcriptional silencing.These methylation patterns were consistent in buccal samples.However, fresh ovarian samples showed partial methylation for both the premutation and normal alleles, regardless of one-week culture, indicating non-random X inactivation with the active premutation allele in peripheral blood and buccal samples but not in ovarian tissues.The second patient with secondary amenorrhea exhibited negligible anti-Mllerian hormone levels and significantly elevated follicle-stimulating hormone (FSH) levels, consistent with hypergonadotropic hypogonadism.Fragile X testing revealed a full variant (>200 CGG repeats) with full methylation and a normal 30 CGG repeats allele with partial methylation.Karyotyping detected 45,X[14]/46,XX [26], and chromosomal microarray analysis noted approximately 30% X chromosome loss, consistent with a diagnosis of mosaic Turner syndrome.