Evaluation of the Limitations of Genomic Diagnostic Methods Through a Case of Isodisomic Maternal UPD14 Detected by SNP Array

Introduction: Uniparental disomy (UPD) is the inheritance of both copies of a chromosome pair from a single parent and can occur in isodisomic or heterodisomic form. Chromosome 14 UPD leads to two different clinical pictures depending on parental origin: maternal UPD14 (Temple syndrome, OMIM #616222) is associated with precocious puberty, obesity, and skeletal anomalies, but diagnosis is difficult due to nonspecific findings; paternal UPD14 (Kagami–Ogata syndrome, OMIM #608149) is characterized by macrosomia, thoracic anomalies, and neonatal respiratory failure. SNP array can detect isodisomic UPD only through loss of heterozygosity (LOH); MLPA cannot provide information about the mechanism of UPD formation. In this case, the limitations of both methods are discussed through a maternal UPD14 case detected by SNP array and confirmed by MS-MLPA.

Materials and Methods: A female patient born in 2017 was evaluated for precocious puberty, obesity, and kyphosis. SNP array performed with the CytoScan™ HT-CMA 96F Assay Training Kit (1.162K) detected isodisomic UPD14 across the entire chromosome 14. Upon clinical concordance, the diagnosis was confirmed with SALSA MLPA Probemix ME032 UPD7-UPD14. Normal copy number and the presence of an entire chromosome 14 of single parental origin were interpreted in favor of maternal isodisomic UPD14.

Discussion: This case demonstrates that SNP array is a powerful tool in UPD screening, but it can mainly capture isodisomy or cases containing isodisomic segments. Heterodisomic UPDs, however, cannot be detected by this method because of their normal copy number and structures that preserve heterozygosity. Therefore, the fact that we identified a UPD case by array does not mean that all UPD cases can be captured with the same approach. This limitation makes visible the diagnostic blind spots in phenotypically nonspecific or very rare cases in which MLPA or another methylation test might not be considered initially. Similarly, MS-MLPA has its own limitations: although it successfully detected the methylation disorder, it cannot distinguish between isodisomy and heterodisomy. This distinction is clinically critical because homozygosity of the entire chromosome in isodisomy carries the risk of unmasking recessive disease alleles on that chromosome. In this particular case, especially for diagnostic efficiency in the prenatal period, planning methylation-sensitive methods such as MS-MLPA at an early stage in the presence of prominent markers such as IUGR in Temple syndrome and polyhydramnios, macrosomia, and placentomegaly in Kagami-Ogata syndrome would increase diagnostic yield.

Conclusion: This case presents an instructive example that highlights not only the diagnostic power but also the limitations of the test methods we used and emphasizes the determining role of clinical findings in diagnosis.

Keywords: Uniparental disomy, Temple syndrome, SNP array, MS-MLPA, Diagnostic limitations