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EXAMINATION OF PRENATAL CASES REFERRED FOR UNIPARENTAL DISOMY 16: REFERRAL PATTERNS, POSITIVE ASSOCIATONS AND KEY FINDINGS

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
Alterations in the imprinting of genes on chromosomes 6, 7, 11, 14, 15 and 20 are well-established as a cause of numerous genetic disorders.  However, for some chromosomes, the literature is not nearly as clear with regards to possible imprinting effects.  Trisomy 16 is a common aneuploidy in which most fetuses are spontaneously lost by the 12th week of gestation.  One line of thought is that fetuses with trisomy 16 that survive longer have some level of correction to disomy.  These may be lost later in gestation due to intrauterine growth retardation (IUGR) resulting from uniparental disomy 16 (UPD 16).  In this study 26 fetuses have been examined for UPD 16.  This study shows the determination of UPD 16 is straightforward and that there does not appear to be a correlation with recognizable phenotypic abnormalities at birth.





 

Methods:
In this study SNP microarray analysis and SNP-UPD analyses were performed on 26 prenatal patients ascertained over the past 6 years.  For fetuses with both parental samples, the Mendelian Inherited Error (MIE) was studied and when only one parent was available, the percent of parental and fetal AB genotypes were examined to determine UPD.  Patients were ascertained because of a variety of indications including: ten with an increased risk of trisomy 16 detected by cfDNA analysis;  one with a prior CVS showing trisomy 16; three with prior PGT-A studies indicating trisomy or monosomy 16; two with parental translocations of 16; and ten because initial SNP analysis revealed a region of homozygosity on chromosome 16 seen in the initial analysis.

Results:
We report that (1) Nine of the twenty-six prenatal analysis were confirmed to have UPD 16, all maternal in origin;  (2) All patients with confirmed UPD had a terminal region of homozygosity (ROH) on chromosome 16,  compared with only one of seventeen patients that demonstrated biparental inheritance;  (3) Three patients referred due to a cfDNA finding of trisomy 16 had confirmed UPD 16 whereas seven others with this same referral showed biparental inheritance (4) While four patients with US abnormalities had confirmed UPD, abnormalities were not consistent among the group. In particular only one in this group was reported to have IUGR, however three in the biparental group also had IUGR; (5) None of the PGT-A, CVS trisomy 16 or prenatal translocation 16 referrals demonstrated UPD 16 and none had a terminal ROH. (6) In addition, one patient (not included above) was referred because of advanced maternal age (AMA). Initial SNP microarray analysis on her fetus revealed a terminal ROH prompting an SNP-UPD analysis revealing segmental UPD, not involving the entire chromosome that was paternal in origin.

Conclusion:
This is the largest study to date examining a group of patients demonstrating UPD 16.  The results have shown that: (1) all UPD16 were of maternal origin with a terminal ROH in all patients with heterodisomy UPD involving the entire chromosome.  This is consistent with maternal meiotic nondisjunction and crossing over, followed by trisomy rescue and our understanding of the origin of trisomy 16; (2) While the referral indication is important for understanding UPD16, the occurrence of a terminal ROH appears to be integral; (3) We found no evidence of correlation of a consistent phenotypic finding with UPD.  However, four patients (one with UPD, three biparental) had IUGR and an abnormal placenta.  This likely reflects trisomy rescue resulting in one case with UPD and three with bi-parental inheritance; thus the findings appear to be most likely attributed to placental trisomy 16 rather than UPD. This study continues to build on our understanding of UPD 16, its origin, and lack of consistent phenotype.

 

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