Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome from one parent. UPD can result in abnormal phenotypes depending on the chromosome involved and type of UPD (isodisomy vs heterodisomy); however, UPD of multiple chromosomes has not been previously described. Here, we report two cases of UPD for multiple chromosomes. Patient 1 is a four-week-old female born at 34 weeks gestation presenting with omphalocele, pulmonary artery stenosis, acute respiratory failure, suck-swallow incoordination, and hyponatremia. Prenatal G-banded karyotype was normal (46,XX). Postnatal chromosomal microarray (CMA) showed segmental absence of homozygosity (AOH) on chromosomes 4, 10, and 14. Microsatellite analysis demonstrated paternal isodisomy/heterodisomy for chromosomes 4, 10, and 14. UPD testing of chromosome 15 showed biparental inheritance, and methylation studies at 11p15 were normal, ruling out mosaic genome-wide UPD. Clinical features of paternal UPD14 partially explains this patient's phenotype. Interestingly, CMA on placenta showed no evidence of low-level trisomy. Patient 2 is an eight-month-old male born at term with intrauterine growth restriction. He had failure to thrive, mild hypotonia, facial dysmorphism, patent ductus arteriosus (PDA), and bilateral 5th finger clinodactyly. CMA demonstrated AOH for the entirety of chromosomes 7 and 9, and mosaic trisomy 21 (∼20%). Microsatellite analysis showed maternal isoUPD7 and paternal isoUPD9. UPD7 (diagnostic of Russell-Silver syndrome) mostly explains this patient's phenotype. The PDA and clinodactyly may be related to mosaic trisomy 21. UPD for multiple chromosomes has not been previously described. Although additional studies are necessary to determine the mechanism of these findings, we hypothesize that these cases represent multiple independent events of trisomy rescue. These cases demonstrate that although extremely rare, the detection of AOH on 2+ chromosomes by CMA may warrant additional clinical/laboratory investigation such as methylation and STR marker analysis, especially when involving chromosomes known to be associated with imprinting disorders.

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DOI: https://doi.org/10.1016/j.cancergen.2022.05.019

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