Mechanisms and Clinical Consequences of UPD
Chromosomes of Clinical Relevance
Paternal UPD6 and transient neonatal diabetes mellitus
Maternal UPD7 and Russell–Silver syndrome
Paternal UPD11 and Beckwith–Wiedemann syndrome
Maternal UPD11 and Russell–Silver syndrome
Maternal UPD14 and Temple syndrome
Paternal UPD14 and Kagami–Ogata syndrome
Maternal UPD15 and Prader–Willi syndrome
Paternal UPD15 and Angelman syndrome
Maternal UPD20 and Mulchandani–Bhoj–Conlin syndrome
Indications for Postnatal UPD Testing
- 1.Patients evaluated for developmental delay/intellectual disability with or without congenital anomalies and found to have a familial or de novo balanced Robertsonian translocation involving chromosome 14 or 15.72.
- 2.Patients evaluated for developmental delay/intellectual disability with or without congenital anomalies and found to have a supernumerary structurally abnormal chromosome derived from chromosome 14 or 15.73.
- 3.Patients with homozygosity for a pathogenic variant causing an autosomal recessive disorder when only one parent is a carrier for that variant, in the absence of other explanations such as intragenic deletion and misattributed relationships.74.
- 4.Patients with TNDM and hypomethylation within the 6q24 DMR region. Testing for UPD6 can be ordered sequentially or simultaneously with MS-MLPA.37.,75.
- 5.Patients with clinical suspicion for RSS. Testing for UPD7 can be ordered sequentially or simultaneously with methylation testing of the IC1 on chromosome 11p15.52.,76.,77.
- 6.Patients with BWS found to have loss of methylation at IC2 and gain of methylation at IC1 at 11p15. It should be noted that first-line molecular testing for BWS should include DNA methylation analysis of IC1 and IC2.23.
- 7.Patients with clinical findings and physical features suggestive of maternal or paternal UPD14. The UPD testing can be ordered sequentially to or simultaneously with the methylation testing.72.,73.
- 8.Patients with PWS or AS with abnormal methylation studies (other than MS-MLPA) who have normal karyotype and CMA results.78.Although large ROH observed by CMA testing is highly suspicious for UPD, it requires confirmation using other methods. It is important to keep in mind that DNA methylation analysis is the first-line testing for PWS and AS.78.
- 9.Patients with PHP1B who have abnormal methylation studies of the DMRs at the GNAS complex locus with normal karyotype and CMA results. In addition, patients with poor growth and feeding difficulties found to have ROH for chromosome 20 on SNP array.
- 10.Female patients who present with unexplained severe manifestations of X-linked conditions and who are found to have homozygosity for a pathogenic variant in an X-linked gene.74.
- 11.Male patients with unexplained father-to-son transmission of an X-linked disorder.3.
Indications For Prenatal UPD Testing
- 1.Level II or level III mosaicism for trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 in amniocentesis or CVS.79.
- 2.Level II or level III mosaicism for trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 in CVS followed by normal karyotype in amniocentesis.80.(Note: Level II (multiple cell pseudomosaicism)81.: same abnormality observed in two or more cells (flask method) or in two or more cells from one or more colonies (in situ) in the same culture.82.Level III (true mosaicism)81.: two or more cells with the same abnormality observed in two or more independent cultures.)
- 3.In the context of preimplantation genetic screening (PGS), a transfer of mosaic embryos with trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 should be followed by prenatal studies including UPD testing.83.,84.,85.Since embryos with a completely normal karyotype are rare in the context of PGS, detection of mosaic aneuploidy does not prohibit transfer. As discussed under UPD mechanisms, one of the processes that leads to mosaicism may involve an initially abnormal conceptus, typically due to a meiotic error, with a subsequent rescue mechanism via a mitotic event generating a normal cell line. Timing of the rescue will determine the distribution of the normal and the abnormal cell lines in the fetus and the placenta. For embryos with mosaicism, rescue may generate a fetus with a normal karyotype but with a risk for UPD.
- 4.Prenatal imaging anomalies consistent with a UPD phenotype. The classic example is the pathognomonic coat-hanger sign in paternal UPD14.86.Omphalocele, macroglossia, visceromegaly, enlarged adrenals, or macrosomia with no obvious mechanism are also typical prenatal findings in BWS.87.Native amniotic fluid is the preferred tissue for UPD11 testing but the degree of mosaicism may not correlate with the true mosaicism in the fetus and therefore the prediction of postnatal phenotypic outcome is challenging. Furthermore, in the case of negative results the presence of mosaic UPD cannot be excluded.80.On the other hand, fetal growth restriction can be considered as a relative indication to test for RSS or Mulchandani–Bhoj–Conlin syndrome but this finding is relatively common and its presence alone should not be an indication.
- 5.Familial or de novo balanced Robertsonian translocation or isochromosome involving chromosome 14 or 15 based on CVS or amniocentesis.72.,88.,89.Both familial and de novo translocations are associated with an increased risk for UPD.
- 6.De novo sSMC with no apparent euchromatic material in the fetus.90.,91.
- 7.Non-Robertsonian translocation between an imprinted chromosome with possible 3:1 disjunction that can lead to trisomy or monosomy rescue or gamete complementation. Although every chromosome abnormality that increases the occurrence of nondisjunction in theory would increase the risk for UPD of the chromosomes involved, there are only very few cases reported.38.,92.
Summary of Clinical and Diagnostic Considerations
- 1.Chromosomes of known clinical relevance for UPD include 6, 7, 11, 14, 15, and 20.
- 2.UPD testing should be considered for:
- a.Evaluation of a subject with clinical, physical, or ultrasonographic features of disorders known to be associated with UPD.
- b.Molecular investigation of a condition that does not follow a typical Mendelian inheritance pattern including recessive and X-linked disorders.
- c.Prenatal or postnatal identification of a structurally abnormal chromosome 14 or 15.
- d.Prenatal trisomy or monosomy mosaicism of a chromosome known to be associated with a UPD phenotype.
- 3.Testing should be performed on DNA collected from the child/fetus and at least one parent using polymorphic markers.
- 4.UPD can be ascertained through analysis of SNP distribution from trio genotype data in the context of exome or genome sequencing. However, unless the UPD analysis is validated by the diagnostic laboratory for clinical use, confirmation by a clinically validated STR-based assay is required. Detection of isodisomic UPD by CMA warrants clinical correlation and further testing to determine parent of origin.
- 5.Reporting of results includes at least two fully informative markers from each chromosome of interest and uses the current ISCN guidelines.25.
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