Distinct Prenatal Diagnostic Pathways to Uniparental Disomy: Insights from Two Cases
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Introduction:
Uniparental disomy (UPD), the inheritance of both copies of a chromosome from one parent, is a rare prenatal finding with potentially significant implications, including imprinting disorders and unmasking of recessive alleles. Prenatal diagnosis of UPD is challenging and often incidental or prompted by comprehensive work-up of nonspecific ultrasound findings.
Case Presentation
Case Presentation:
Case 1: A 38-year-old pursued amniocentesis for the indication of advanced maternal age. Ultrasound evaluation was remarkable for an inability to visualize the cavum septum pellucidum at 22w5d.
Case 2: A 40-year-old presented with fetal growth restriction (FGR). Estimated fetal weight was at the 10th percentile at 20 weeks and the 3.6th percentile at 23 weeks. The placenta appeared sonographically normal, despite increased umbilical artery Doppler indices.
Diagnostic Workup
Diagnostic Workup:
Case 1: SNP-microarray on amniocytes revealed two large regions of homozygosity (ROH), suggestive of UPD of chromosome 1. Neither SNP-microarray, extended karyotype analysis of 45 cells, nor “all chromosome” prenatal cell-free DNA (cfDNA) screening identified trisomy 1. Due to the significantly increased risk for a recessive disorder (if the patient or her partner were heterozygous for a pathogenic variant in a gene within the ROH), prenatal exome sequencing (ES) was performed concurrently with UPD studies. ES returned negative. Trio-based UPD studies confirmed maternal UPD1.
Case 2: “All chromosome” prenatal cfDNA screening returned positive for trisomy 14. The patient then pursued amniocentesis. Neither prenatal karyotype nor SNP-microarray demonstrated trisomy 14, suggesting confined placental mosaicism. However, SNP-microarray revealed a large ROH on chromosome 14. Maternal UPD14 is highly suspected, which would be consistent with a diagnosis of Temple syndrome, an imprinting disorder. Confirmatory UPD studies are pending.
Treatment and Management
Treatment and Management:
Case 1: DIRAS3 is a maternally-imprinted tumor suppressor gene on chromosome 1. Counseling included a possibly elevated tumor risk for the fetus. The patient elected pregnancy continuation.
Case 2: Counseling focused on the potential diagnosis of Temple syndrome, including natural history, postnatal evaluation, and management, were this diagnosis to be confirmed. FGR may be secondary to Temple syndrome, placental mosaicism for trisomy 14, or both. The patient is continuing the pregnancy.
Outcome and Follow-Up
Outcome and Follow-up:
Case 1: Fetal MRI at 25w0d was normal with no identified central nervous system abnormality. The fetus was found to be large for gestational age in the third trimester. The patient was induced at 39w6d and delivered a normal appearing 4.97 kg infant. Neonatal hypoglycemia resolved prior to discharge on day of life 3.
Case 2: The patient is being closely followed for FGR (which may preclude full-term delivery) with nonstress testing, umbilical artery Dopplers, and serial fetal growth sonograms with anatomic re-assessments.
Discussion
Discussion:
While ascertainment and outcomes differed, both cases underscore the utility of SNP-microarray in identifying ROH as a clue to uncovering uniparental isodisomy interspersed among heterodisomy. Meiotic recombination between homologs in meiosis I followed by nondisjunction in meiosis II and post-zygotic trisomy rescue form the likely trio of mechanistic events underlying this observation. SNP-microarray should be offered to all patients considering prenatal diagnosis, not only for its ability to detect copy number variants, but for detection of ROH, which should prompt further work-up for UPD and its functional correlates, including imprinting defects, homozygosity of a recessive allele, and aneuploidy mosaicism.
Conclusion
Conclusion:
Prenatal UPD detection, whether targeted or incidental, requires nuanced counseling surrounding the etiology, clinical relevance, and appropriate investigative steps. While UPD is a rare finding, aneuploidy is not, especially in the context of advanced maternal age. As cases such as the two presented here come to light more frequently with the expanding application of high-resolution assays, future research should explore optimizing prenatal UPD detection and its impact on clinical outcomes.
Introduction:
Uniparental disomy (UPD), the inheritance of both copies of a chromosome from one parent, is a rare prenatal finding with potentially significant implications, including imprinting disorders and unmasking of recessive alleles. Prenatal diagnosis of UPD is challenging and often incidental or prompted by comprehensive work-up of nonspecific ultrasound findings.
Case Presentation
Case Presentation:
Case 1: A 38-year-old pursued amniocentesis for the indication of advanced maternal age. Ultrasound evaluation was remarkable for an inability to visualize the cavum septum pellucidum at 22w5d.
Case 2: A 40-year-old presented with fetal growth restriction (FGR). Estimated fetal weight was at the 10th percentile at 20 weeks and the 3.6th percentile at 23 weeks. The placenta appeared sonographically normal, despite increased umbilical artery Doppler indices.
Diagnostic Workup
Diagnostic Workup:
Case 1: SNP-microarray on amniocytes revealed two large regions of homozygosity (ROH), suggestive of UPD of chromosome 1. Neither SNP-microarray, extended karyotype analysis of 45 cells, nor “all chromosome” prenatal cell-free DNA (cfDNA) screening identified trisomy 1. Due to the significantly increased risk for a recessive disorder (if the patient or her partner were heterozygous for a pathogenic variant in a gene within the ROH), prenatal exome sequencing (ES) was performed concurrently with UPD studies. ES returned negative. Trio-based UPD studies confirmed maternal UPD1.
Case 2: “All chromosome” prenatal cfDNA screening returned positive for trisomy 14. The patient then pursued amniocentesis. Neither prenatal karyotype nor SNP-microarray demonstrated trisomy 14, suggesting confined placental mosaicism. However, SNP-microarray revealed a large ROH on chromosome 14. Maternal UPD14 is highly suspected, which would be consistent with a diagnosis of Temple syndrome, an imprinting disorder. Confirmatory UPD studies are pending.
Treatment and Management
Treatment and Management:
Case 1: DIRAS3 is a maternally-imprinted tumor suppressor gene on chromosome 1. Counseling included a possibly elevated tumor risk for the fetus. The patient elected pregnancy continuation.
Case 2: Counseling focused on the potential diagnosis of Temple syndrome, including natural history, postnatal evaluation, and management, were this diagnosis to be confirmed. FGR may be secondary to Temple syndrome, placental mosaicism for trisomy 14, or both. The patient is continuing the pregnancy.
Outcome and Follow-Up
Outcome and Follow-up:
Case 1: Fetal MRI at 25w0d was normal with no identified central nervous system abnormality. The fetus was found to be large for gestational age in the third trimester. The patient was induced at 39w6d and delivered a normal appearing 4.97 kg infant. Neonatal hypoglycemia resolved prior to discharge on day of life 3.
Case 2: The patient is being closely followed for FGR (which may preclude full-term delivery) with nonstress testing, umbilical artery Dopplers, and serial fetal growth sonograms with anatomic re-assessments.
Discussion
Discussion:
While ascertainment and outcomes differed, both cases underscore the utility of SNP-microarray in identifying ROH as a clue to uncovering uniparental isodisomy interspersed among heterodisomy. Meiotic recombination between homologs in meiosis I followed by nondisjunction in meiosis II and post-zygotic trisomy rescue form the likely trio of mechanistic events underlying this observation. SNP-microarray should be offered to all patients considering prenatal diagnosis, not only for its ability to detect copy number variants, but for detection of ROH, which should prompt further work-up for UPD and its functional correlates, including imprinting defects, homozygosity of a recessive allele, and aneuploidy mosaicism.
Conclusion
Conclusion:
Prenatal UPD detection, whether targeted or incidental, requires nuanced counseling surrounding the etiology, clinical relevance, and appropriate investigative steps. While UPD is a rare finding, aneuploidy is not, especially in the context of advanced maternal age. As cases such as the two presented here come to light more frequently with the expanding application of high-resolution assays, future research should explore optimizing prenatal UPD detection and its impact on clinical outcomes.
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