The maternal uniparental disomy of chromosome 6 (upd(6)mat) “phenotype”: result of placental trisomy 6 mosaicism?

Abstract

BackgroundMaternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding and its clinical relevance is currently unclear. Based on clinical data from two new cases and patients from the literature, the pathogenetic significance of upd(6)mat is delineated.MethodsOwn cases were molecularly characterized for isodisomic uniparental regions on chromosome 6. For further cases with upd(6)mat, a literature search was conducted and genetic and clinical data were ascertained.ResultsComparison of isodisomic regions between the new upd(6)mat cases and those from four reports did not reveal any common isodisomic region. Among the patients with available cytogenetic data, five had a normal karyotype in lymphocytes, whereas a trisomy 6 (mosaicism) was detected prenatally in four cases. A common clinical picture was not obvious in upd(6)mat, but intrauterine growth restriction (IUGR) and preterm delivery were frequent.ConclusionA common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause.

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

“…Both hUPD and iUPD can result in imprinting disorders if they involve imprinted genes, which are characterized by monoallelic expression in a parent‐of‐origin‐specific manner. To date, approximately 100 imprinted genes, implicated mainly in the control of fetal and postnatal growth, are known (Eggermann et al ., ). As our patient has no paternal contribution from the whole of chromosome 4, we sought to explore the presence of maternally imprinted genes on chromosome 4.…”

Syndromic Disorders Caused by Disturbed Human Imprinting

“…However, homozygosity of a recessive allele and/or placental trisomy 6 mosaicism is likely to be the pathogenic mechanism in some of these patients. These data suggest that a specific imprinting disorder associated with UPD(6)mat does not exist and that the heterogeneous clinical features in UPD(6) mat patients are either caused by placental trisomy 6, undetected trisomy 6 cell lines or by homozygosity for recessive mutations (5,17). However, given the small number of patients described to date and the presence of an imprinted region on chromosome 6q24 further studies are required to clarify this contentious issue.…”

Uniparental Disomy and Imprinting Disorders

“…In this situation, the UPD is regarded as a biomarker for the chromosomal alteration (e.g. upd(6)mat and upd(16)mat) [20,33] rather than as the cause of the aberrant phenotype. Moreover, the combination of both chromosomal alterations and UPDs can cause heterogeneous clinical presentations, obscuring clinical diagnosis or mimicking known disorders.…”

“…They include well-known congenital disorders like PWS, AS, Beckwith-Wiedemann, and Silver-Russell syndrome, as well as rare disorders that are lesser-known such as transient neonatal diabetes mellitus; pseudohypoparathyroidism; or the recently described Temple, Kagami-Ogata, Schaaf-Yang, and Mulchandani-Bhoj-Conlin syndromes. Recently, upd(6)mat, upd(16)mat, and upd(7)pat have been suggested to be associated with imprinting disorders [20,33,34]. However, the influence of trisomy 6 or 16 mosaicism on the phenotype has been suggested for upd(6)mat and upd (16)mat, based on the genetic findings and the clinical heterogeneity of the carriers.…”