Abstract
Paternal uniparental disomy 14 (UPD(14)pat) and epimutations and microdeletions affecting the maternally derived 14q32.2 imprinted region lead to a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with a coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. In this study, we performed comprehensive clinical studies in patients with UPD(14)pat (n=23), epimutations (n=5), and microdeletions (n=6), and revealed several notable findings. First, a unique facial appearance with full cheeks and a protruding philtrum and distinctive chest roentgenograms with increased coat-hanger angles to the ribs constituted the pathognomonic features from infancy through childhood. Second, birth size was well preserved, with a median birth length of ±0 SD (range, −1.7 to +3.0 SD) and a median birth weight of +2.3 SD (range, +0.1 to +8.8 SD). Third, developmental delay and/or intellectual disability was invariably present, with a median developmental/intellectual quotient of 55 (range, 29–70). Fourth, hepatoblastoma was identified in three infantile patients (8.8%), and histological examination in two patients showed a poorly differentiated embryonal hepatoblastoma with focal macrotrabecular lesions and well-differentiated hepatoblastoma, respectively. These findings suggest the necessity of an adequate support for developmental delay and periodical screening for hepatoblastoma in the affected patients, and some phenotypic overlap between UPD(14)pat and related conditions and Beckwith–Wiedemann syndrome. On the basis of our previous and present studies that have made a significant contribution to the clarification of underlying (epi)genetic factors and the definition of clinical findings, we propose the name ‘Kagami–Ogata syndrome' for UPD(14)pat and related conditions.
Highlights
IntroductionHuman chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1, and maternally expressed genes (MEGs) such as MEG3 (alias, GTL2), RTL1as (RTL1 antisense), MEG8, snoRNAs, and microRNAs (Supplementary Figure S1). The parental origin-dependent expression patterns are regulated by the germline-derived primary DLK1MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR. Both DMRs are hypermethylated after paternal transmission and hypomethylated after maternal transmission in the body; in the placenta, the IG-DMR alone remains as a DMR with the same methylation pattern in the body, while the MEG3-DMR does not represent a differentially methylated pattern. Consistent with such methylation patterns, the hypomethylated IG-DMR and MEG3-DMR of maternal origin function as imprinting control centers in the placenta and the body, respectively, and the IG-DMR behaves hierarchically as an upstream regulator for the methylation pattern of the MEG3-DMR in the body, but not in the placenta.3,4Paternal uniparental disomy 14 (UPD[14]pat) (OMIM #608149) results in a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. These clinical features are caused by epimutations (hypermethylations) and microdeletions affecting the maternally derived IG-DMR and/or MEG3-DMR (Supplementary Figure S1)
The 23 patients of UPD-group were divided into three subtypes in terms of UPD generation mechanisms by microsatellite analysis, as reported previously:9 [1] 13 patients with monosomy rescue (MR) or postfertilization mitotic error (PE)-mediated UPD[14]pat indicated by full isodisomy (UPD-S1); [2] a single patient with PE-mediated UPD[14]pat demonstrated by segmental isodisomy (UPD-S2); and [3] nine patients with trisomy rescue (TR) or gamete complementation (GC)-mediated UPD[14]pat revealed by heterodisomy for at least one locus (UPD-S3) (Supplementary Figure S2) (it is possible that some patients classified as UPD-S1 may have a cryptic heterodisomic region(s) and belong to UPD-S3)
The results indicate that the facial features with full cheeks and protruding philtrum and the thoracic roentgenographic findings with increased coat-hanger angle (CHA) to the ribs represent the pathognomonic features of UPD[14]pat and related conditions from infancy through the childhood
Summary
Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1, and maternally expressed genes (MEGs) such as MEG3 (alias, GTL2), RTL1as (RTL1 antisense), MEG8, snoRNAs, and microRNAs (Supplementary Figure S1). The parental origin-dependent expression patterns are regulated by the germline-derived primary DLK1MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR. Both DMRs are hypermethylated after paternal transmission and hypomethylated after maternal transmission in the body; in the placenta, the IG-DMR alone remains as a DMR with the same methylation pattern in the body, while the MEG3-DMR does not represent a differentially methylated pattern. Consistent with such methylation patterns, the hypomethylated IG-DMR and MEG3-DMR of maternal origin function as imprinting control centers in the placenta and the body, respectively, and the IG-DMR behaves hierarchically as an upstream regulator for the methylation pattern of the MEG3-DMR in the body, but not in the placenta.3,4Paternal uniparental disomy 14 (UPD[14]pat) (OMIM #608149) results in a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. These clinical features are caused by epimutations (hypermethylations) and microdeletions affecting the maternally derived IG-DMR and/or MEG3-DMR (Supplementary Figure S1). The parental origin-dependent expression patterns are regulated by the germline-derived primary DLK1MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR.2,3 Both DMRs are hypermethylated after paternal transmission and hypomethylated after maternal transmission in the body; in the placenta, the IG-DMR alone remains as a DMR with the same methylation pattern in the body, while the MEG3-DMR does not represent a differentially methylated pattern.. Paternal uniparental disomy 14 (UPD[14]pat) (OMIM #608149) results in a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios.. Paternal uniparental disomy 14 (UPD[14]pat) (OMIM #608149) results in a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios.2,5 These clinical features are caused by epimutations (hypermethylations) and microdeletions affecting the maternally derived IG-DMR and/or MEG3-DMR (Supplementary Figure S1). Loss of the maternally inherited MEG3-DMR alone leads to a typical UPD[14]pat body phenotype and apparently normal placental phenotype, whereas loss of the maternally derived IG-DMR alone or both DMRs results in a typical body and placental UPD[14]pat phenotype, consistent with the methylation patterns of the two DMRs. correlations between clinical features and deleted segments have indicated the critical role of excessive RTL1 (but not DLK1) expression in phenotypic development. Such an excessive RTL1 expression is primarily due to loss of functional RTL1as-encoded microRNAs that act as a trans-acting repressor for RTL1 expression. the RTL1 expression level is ~ 5 times, rather than 2 times, increased in placentas with UPD[14]pat
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