The clinical phenotype of mosaicism for genome‐wide paternal uniparental disomy: Two new reports

Abstract

Recently, mosaicism for genome-wide paternal uniparental disomy (patUPD), attributed to androgenetic/biparental mosaicism, has been shown to underlie placental mesenchymal dysplasia (PMD), a distinctive cystic placental phenotype. Manifestations of Beckwith-Wiedemann syndrome (BWS) have been observed in approximately one-third of fetuses or liveborn infants from pregnancies complicated by PMD. There are very few reports describing liveborn individuals with proven mosaicism for genome-wide patUPD in somatic tissues. We report two further children with complex phenotypes including some findings of BWS, congenital hyperinsulinemic hypoglycemia, prolonged feeding difficulty and failure to thrive in infancy. The first developed short stature, bilateral pheochromocytomas and progressive arterial stenoses, and the second had congenital adrenal cysts, and later developed hepatoblastoma and patchy hyperpigmentation. Leukocyte DNA methylation studies of KCNQ1OT1/LIT1 and H19 loci (11p15.5) showed almost complete loss of maternal methylation (LOM) in patient 1 and partial LOM in patient 2. Microsatellite marker panels showed whole chromosome 11 patUPD. SNP array studies in both were consistent with mosaic genome-wide patUPD in leukocytes, while fibroblast DNA in Patient 1 showed biparental inheritance. This report further illustrates the clinical consequences of mosaicism for genome-wide patUPD, which results in complex and variable phenotypes. Studies for genome-wide UPD should be considered in individuals with atypical UPD phenotypes.

Androgenetic/biparental mosaicism in a girl with Beckwith–Wiedemann syndrome-like and upd(14)pat-like phenotypes

“…Indeed, an androgenetic cell lineage has been identified in six liveborn individuals with variable phenotypes. [3][4][5][6][7] All the androgenetic cell lineages have a 46,XX karyotype, and this is consistent with the lethality of an androgenetic 46,YY cell lineage.…”

“…[3][4][5][6][7] In this context, leukocytes are preferentially utilized for genetic analyses in human patients, and detailed examinations such as analyses of plural DMRs are necessary to detect an androgenetic cell lineage. Thus, the hitherto identified patients would be limited to those who had androgenetic cells as a predominant cell lineage in leukocytes probably because of a stochastic event and received detailed molecular studies.…”

Mosaics and moles

“…Indications of mosaicism/ chimerism with an androgenetic and a biparental cell population have been observed both in HMs, [12][13][14][15][16], present study in placentas displaying PMD, 18,[23][24][25] and in fetuses/children with malformations or growth abnormalities mimicking (part of) the Beckwith-Wiedemann phenotype. [25][26][27][28][29][30] The phenotype seems to correlate with the localization of the androgenetic cells. In the cases presenting with malformations in a fetus/child, the androgenetic cells were observed in the fetus/child, and in PMD, the androgenetic cells have been observed predominantly in the placental vessels, chorion, and mesenchymal cells.…”

Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith–Wiedemann syndrome and ovarian steroid cell tumour

“…In addition to the aforementioned BWS features, single genome-wide patUPD carriers present symptoms overlapping with those of other imprinting disorders. 6,7 As aforementioned, the BWS phenotype does not only comprise dysmorphic and metabolic features, but is also associated with a significantly increased risk for embryonal tumours. As a result, the majority of the genome-wide patUPD patients develop BWSassociated cancers, such as WT or hepatoblastoma.…”

“…In contrast to non-mosaic genome-wide patUPD, its mosaic status-also known as androgenic/biparental mosaicism-is compatible with life and has been reported for several times (Table 1). [1][2][3][4][5][6][7] For non-mosaic genomewide patUPD, different formation mechanisms have been suggested, which mainly occur from prefertilisation stages (for review, refer Van den Veyver and Al-Hussaini 8 and Golubovsky 9 ). Mosaic genome-wide patUPD is probably the result of a normal conception followed by post-zygotic errors.…”