Umut Altunoğlu, Tuğba Saraç Sivrikoz, Atıl Yüksel, Hülya Kayserili
The Journal of European Internal Medicine Professionals - 2025;3(4):160-164
Background: Prenatal exome sequencing (pES) is recommended mainly for fetuses with major or multiple structural anomalies when conventional karyotyping and chromosomal microarray are non-diagnostic. Outside these indications, its clinical value is uncertain. Methods: We retrospectively reviewed 10 fetuses tested with pES at our center (2016-2025) despite lacking guideline-based indications. Indications included advanced maternal age (n=1), sex-chromosome anomalies (n=5), parental gonadal mosaicism risk (n=2), and isolated soft ultrasonographic marker (n=2). All cases had karyotype and/or chromosomal microarray (CMA) before pES. Results: One fetus carried a pathogenic SETD5 (NM_001080517.3) c.1541del, p.(Lys514Argfs*2) variant, along with 45,X/46,XY mosaicism and transient ascites/pleural effusion. The SETD5 variant was considered incidental in the prenatal context, though it influenced management and led to medical termination. A second fetus had a maternally inherited heterozygous NSD1 (NM_022455.4) c.2410C>T, p.(Pro804Ser) variant of uncertain significance supporting pregnancy continuation, but the pregnancy was terminated in an external center. One other fetus was lost to follow-up; all other live-born infants appeared normal on postnatal examination. Conclusion: In this small "out-of-indication" series, pES was management-changing in one pregnancy and created uncertainty in another, which complicated the family's decision-making process. The latter finding aligns with current recommendations discouraging pES in low-risk antenatal settings due to its limited yield. Nonetheless, in select situations involving unresolved diagnostic ambiguity, pES may still uncover variants with potential relevance to counseling and management.
