Prenatal to Postnatal Outcomes in a Whole Maternal Isodisomy 6: A Case Report with Favorable Prognosis and Literature review

Technical Summary: Prenatal to Postnatal Outcomes in a Whole Maternal Isodisomy 6 Case

Problem Statement
Whole maternal isodisomic uniparental disomy of chromosome 6 (UPiD6) is an exceptionally rare genetic phenomenon, with only approximately ten cases documented to date. While maternal UPD6 is known to be associated with diverse clinical manifestations, including intrauterine growth restriction (IUGR), congenital malformations, and autosomal recessive disorders, the majority of reported cases have resulted in poor prognoses. A significant gap exists in understanding the specific etiology of IUGR in these cases and whether a favorable postnatal outcome is possible when pathogenic single-gene variants and copy number variations (CNVs) are excluded. Furthermore, the mechanisms linking UPD6 to placental dysfunction and the specific role of confined placental mosaicism (CPM) in this context require further elucidation.

Methodology
The study presents a detailed case report of a female fetus diagnosed prenatally with whole maternal UPiD6, combined with a comprehensive literature review of 26 maternal UPD6 cases.

• Case Subject: A 27-year-old woman underwent selective amniocentesis at 19 weeks gestation following a non-invasive prenatal test (NIPT) suggesting chromosomal 6 abnormalities (specifically microdeletion/duplication signals).
• Genetic Analysis:
  • Karyotyping: Cultured amniocytes were analyzed via G-banding (400-band resolution).
  • Chromosomal Microarray Analysis (CMA): Performed on uncultured amniocytes, parental blood, umbilical cord, and multiple placental sites (fetal and maternal counterparts, inner and lateral sides). This utilized the Affymetrix® Cytoscan™ 750K array to detect CNVs and regions of homozygosity (ROH).
  • Trio Whole-Exome Sequencing (trio-WES): Conducted on amniotic fluid and parental blood to exclude pathogenic sequence variants (SNVs) and recessive disorders within homozygous regions.
  • Infection and Maternal Screening: PCR for fetal infections (CMV, toxoplasmosis, HSV) and serological testing for maternal autoimmune and thrombophilic causes of IUGR were performed.
• Placental Histopathology: The placenta and umbilical cord were fixed, embedded, and stained with H&E for microscopic examination of villous maturity and pathology.
• Clinical Follow-up: The pregnancy was managed by a multidisciplinary team. Postnatal monitoring included anthropometric measurements, neurodevelopmental screening (Denver Developmental Screening Test), and thyroid function tests up to 27 months of age.
• Literature Review: A systematic search of PubMed, Ovid Embase, and Ovid Medline (up to July 2026) identified 26 maternal UPD6 cases for phenotypic and genetic comparison.

Key Results

• Genetic Findings:
  • Fetus: CMA of amniotic fluid and umbilical cord confirmed whole maternal isodisomy 6 (UPiD6) with no pathogenic CNVs or SNVs. Trio-WES excluded recessive disorders on chromosome 6.
  • Placenta: CMA of multiple placental samples revealed confined placental mosaicism (CPM). Specifically, the placenta showed mosaic large-segment deletions and duplications of 6p (loss and gain mosaicism) alongside regions of homozygosity. The complexity of mosaicism was highest in the placental maternal counterpart and decreased toward the umbilical cord, suggesting a post-zygotic origin of the UPiD6.
• Clinical Phenotype:
  • Prenatal: The fetus developed IUGR starting at 26 weeks, characterized by abdominal circumference below the 10th percentile. Placental pathology revealed a small placenta (<3rd percentile), villous immaturity, distal villous dysplasia, and multifocal infarctions.
  • Postnatal: The infant was born at 37 weeks via cesarean section with severe low birth weight (1640 g, < -3 SD) and length (41 cm, < -3 SD).
  • Outcome: Despite severe prenatal IUGR, the infant exhibited significant catch-up growth. By 4 months, growth parameters stabilized between -2 SD and 0 SD. Neurodevelopment was normal at 12 months. A transient subclinical hypothyroidism resolved by 25 months. At 27 months, the child showed no major structural anomalies or developmental delays.
• Literature Review: Among 26 reviewed maternal UPD6 cases, 88.5% (23/26) presented with IUGR. Most cases were associated with pathogenic gene variants or structural anomalies and had poor outcomes. This case represents the first documented instance of whole maternal UPiD6 with isolated IUGR and a favorable neurodevelopmental outcome following the exclusion of pathogenic variants.

Significance and Conclusions
The paper claims that this case demonstrates that a favorable postnatal outcome is achievable in fetuses with whole maternal UPiD6, provided that comprehensive prenatal genetic testing (CMA and WES) excludes pathogenic CNVs and SNVs. The study suggests that the observed IUGR and placental dysfunction in this case were likely driven by confined placental mosaicism involving deleterious large-segment deletions and duplications of chromosome 6p, rather than by unmasking of autosomal recessive disorders or imprinting defects (though the latter remains a theoretical possibility requiring further transcriptomic analysis).

The authors conclude that the gradient of mosaicism observed from the placenta to the fetus supports a "post-zygotic rescue" mechanism, where an early chromosomal imbalance was corrected in the fetal lineage but persisted in the placenta. This case highlights the importance of placental genetic and pathological analysis in understanding the etiology of IUGR in UPD cases and offers a more optimistic prognosis for similar cases where pathogenic variants are ruled out.