Recurrent Male-Selective Perinatal Death in a Family with a Paternal Yqh+ Y-Chromosome Heterochromatin Variant: A Case Report and Hypothesis [R1]

Abstract

Background: Heterochromatin variants of chromosome Y (Yqh+) are classified by international cytogenetic nomenclature as benign polymorphisms. However, several case-control studies have reported a higher frequency of these variants among couples with recurrent pregnancy loss, and a plausible sex-specific mechanism has not been firmly established. Case presentation: We describe a couple with two dizygotic twin pregnancies — one conceived by in-vitro fertilization and one spontaneous — in which all three male conceptuses died (one neonatal death, two intrauterine fetal deaths at approximately 24-26 weeks), while the single female co-twin from the first pregnancy survived and remains healthy. Transmission of the paternally derived Yqh+ variant to the three affected male conceptuses was not directly demonstrated by molecular or cytogenetic testing of the conceptuses themselves and is inferred from the expected pattern of non-recombining paternal Y-chromosome transmission. [R2] With only three affected male conceptuses and one surviving female conceptus, this male-only pattern could plausibly have arisen by chance and does not by itself establish a reproducible sex-specific association. [R17] Parental duo whole exome sequencing did not identify a parental variant providing a plausible monogenic explanation for the phenotype [R9] ; incidental heterozygous carrier findings in unrelated autosomal recessive genes (maternal UPB1; paternal PAH) and an unrelated maternal autosomal dominant DSPP variant were reported but do not account for the pattern of loss, since the two recessive conditions involve non-overlapping genes. Maternal autoimmune (17-antibody ANA panel), coagulation, and a partial antiphospholipid panel (anticardiolipin IgM and lupus anticoagulant only, not meeting full Sydney diagnostic criteria) [R11] were negative or within normal limits. Parental karyotyping showed a normal female karyotype and a paternal karyotype of 46,XY,Yqh+. Conclusion: The exclusively male-selective pattern of loss across two independent twin pregnancies, combined with investigations that did not identify [E10] a clear alternative maternal autoimmune, thrombophilic, or shared monogenic explanation, raises the hypothesis-generating — and unconfirmed — possibility that the paternal Yqh+ variant contributed to this family's reproductive outcome, possibly through a paternal meiotic/gametogenic mechanism or a post-fertilization Y-linked developmental effect [E3] rather than a coding-sequence mechanism. This single-family observation cannot establish causality and the observed pattern could reflect chance given the small number of affected conceptuses [E17] ; it should prompt further study, including molecular cytogenetic characterization of Yqh+ subvariants and, where future pregnancies occur, direct fetal/products-of-conception karyotyping.