Kagami-Ogata syndrome: UPD(14)pat (OMIM608149) and related conditions
By Tsutomu Ogata (as of 22 January 2015)
Kagami-Ogata syndrome (KOS) refers to UPD(14)pat (OMIM608149) and related conditions (Kagami et al. 2015). It is associated with a unique constellation of clinical features and is caused by (epi)genetic aberrations affecting the imprinted region at chromosome 14q32.2.
Historically, Wang et al. (1991) first identified uniparental paternal heterodisomy for chromosome 14 in a carrier with unbalanced 13/14 Robertsonian translocation. Subsequently, Kagami et al. (2008) found epimutations and microdeletions involving the 14q32.2 imprinted region in patients with UPD(14)pat-compatible phenotype. To date, 37 patients with UPD(14)pat, five patients with epimutations, and nine patients with microdeletions have been reported in the literature (reviewed in Kagami et al. 2015).
The chromosome 14q32.2 imprinted region
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 (da Rocha et al. 2008). The parental origin dependent expression patterns are regulated by the DLK1–MEG3 intergenic differentially methylated region (IG-DMR) and the MEG3-DMR (Kagami et al. 2008, 2010). 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 (Kagami et al. 2008, 2010). The methylation patterns are consistent with the IG-DMR being the germ-line derived primary DMR and the MEG3-DMR being the postfertilization-derived secondary DMR. This imprinted region is highly conserved on the distal part of the mouse chromosome 12 (Kaneko-Ishino et al. 2006). One difference between the human and the mouse homologous imprinted regions would be that human DIO3 is likely to show a biallelic non-imprinted expression pattern, whereas mouse Dio3 undergoes partial imprinting (Tsai et al 2002; Kagami et al. 2012b).
Consistent with such methylation patterns, the hypomethylated IG-DMR and the MEG3-DMR of maternal origin function as imprinting control centers in the placenta and the body respectively (Kagami et al. 2010). Furthermore, 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 (Kagami et al. 2010; Beygo et al. 2014). Thus, the MEG3-DMR can remain unmethylated in the body only when the IG-DMR is unmethylated.
One notable finding in this 14q32.3 imprinted region is that maternally expressed RTL1as-encoded microRNAs function as a trans-acting repressor for paternally expressed RTL1. Thus, RTL1 expression is increased in the absence of functional RTL1as. Indeed, RTL1 expression level is ~5 times, rather than 2 times, increased in placentas with UPD(14)pat accompanied by two copies of functional RTL1 and no functional RTL1as (Kagami et al. 2012b). This implies that the RTL1 expression level is ~2.5 times increased in the absence of functional RTL1as-encoded microRNAs. The excessive RTL1 expression appears to constitute the primary factor for the development of KOS clinical findings (see below). Such interaction between Rtl1 and Rtl1as-encoded microRNAs has also been shown in the mouse (Seitz et al. 2003; Davis et al. 2005).
Clinical findings ↓
KOS is associated with a unique constellation of clinical features that are quite similar among patients with UPD(14)pat, those with epimutations, and those with microdeletions (Kagami et al. 2015). Representative findings include:  polyhydramnios that is probably ascribed to placentomegaly as a cause of excessive production of amniotic fluid and impaired swallowing as a cause of reduced absorption of amniotic fluid;  placentomegaly that is accompanied by swollen vascular endothelial cells and hypertrophic pericytes in the terminal chorionic villi;  well preserved prenatal growth with excessive birth weights that are possibly due to muscular hypertrophy;  rather compromised postnatal growth that is explained by severely poor body condition after birth;  unique facial appearance with full cheeks and protruding philtrum;  distinctive chest roentgenograms with increased coat-hanger angles (CHA) to the ribs and decreased ratios of the mid to widest thorax diameter (M/W ratio);  abdominal wall defects such as omphalocele and diastasis recti;  developmental delay and/or intellectual disability that is invariably found in affected patients;  poor sucking and swallowing that usually require gastric tube feeding;  hepatoblastoma that has been identified in 8.8% of patients during infancy; and  mortality rate of 20–25% that has been primarily observed in patients less than four years at the time of respiratory infections (Kagami et al. 2015).
Of these, the facial “Gestalt” with full cheeks and protruding philtrum, and distinctive chest roentgenograms with increased CHAs and decreased M/W ratios, represent the pathognomonic features in infancy, especially when they appear in association with episodes of polyhydramnios and/or placentomegaly (Kagami et al. 2015). Furthermore, the facial “Gestalt” and increased CHAs constitute the diagnostic hallmarks throughout childhood, although the M/W ratios normalize with age (Kagami et al. 2015).
Notably, KOS share several clinical features with Beckwith-Wiedemann syndrome (BWS). For example, polyhydramnios, placentomegaly, abdominal wall defects (omphalocele), and hepatoblastoma are often observed in both KOS and BWS (Kagami et al. 2015). Thus, KOS may be worth considering in atypical or underlying factor-unknown BWS.
Molecular findings ↓
To date, KOS is caused by UPD(14)pat (~65%), by epimutations affecting the IG-DMR and the MEG3-DMR (~15%), or by microdeletions involving the IG-DMR and/or the MEG3-DMR (~20%) (Kagami et al. 2012a). Furthermore, of underlying factors leading to UPD(14)pat, i.e., trisomy rescue (TR), gamete complementation (GC), monosomy rescue (MR), and post-fertilization mitotic error (PE), MR/PE type UPD(14)pat is predominantly identified in patients born to aged mothers ((≥35 years). This implies that advanced maternal age at childbirth as a predisposing factor for the generation of nullisomic oocytes through non-disjunction at meiosis 1 may be involved in the development of MR-mediated UPD(14)pat (Kagami et al. 2012a).
In considering the underlying (epi)genetic factors involved in the development of clinical features in KOS, molecular and clinical data in patients with microdeletions are informative. Indeed, microdeletions are accompanied by variable expression dosages of the imprinted genes depending on the size of the deleted regions., e.g. 1 ´ (normal) or 2 ´ DLK1 expression dosage and ~2.5 ´ or ~5 ´ RTL1 expression dosage as well as absent MEGs expression in the body, and 1 ´ (normal) or 2 ´ DLK1 expression dosage and ~1 ´ or ~2.5 ´ RTL1 expression dosage as well as absent or 1 ´ (normal) MEGs expression in the placenta (Kagami et al. 2015). By contrast, UPD(14)pat and epimutations are invariably associated with 2 ´ (doubled) DLK1 expression dosage and ~5 ´ RTL1 expression dosage as well as absent MEGs expression in both the body and the placenta.
To date, (epi)genotype-phenotypes analyses in patients with various patterns of microdeletions have indicated the following:  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 and the hierarchical interaction between the two DMRs (Kagami et al. 2010; Beygo et al. 2014);  correlations between clinical features and deleted segments have indicated the critical role of excessive RTL1 (but not DLK1) expression in phenotypic development (Kagami et al. 2008); and  since clinical features are comparable among patients with UPD(14)pat, those with epimutations, and those with various patterns of microdeletions, it is likely that ~2.5 ´ RTL1 expression common to all the patients is the primary factor for the phenotypic development in both the body and the placenta (Kagami et al. 2015).
Although significant progress is observed in the clarification of underlying (epi)genetic factors and the definition of clinical findings, several matters remain to be clarified, including  how the IG-DMR functions as the imprinting center in the placenta;  how the IG-DMR functions as the imprinting center in the placenta; and  why the MEG3-DMR can stay unmethylated only in the presence of the unmethylated IG-DMR. Furthermore, although it is possible that a tiny deletion involving RTLas but not the DMRs leads to KOS phenotype primarily because of increased RTL1 expression level, there has been no report describing a patient with such a microdeletion. Further studies will permit to elucidate the underlying factors for the hitherto unresolved matters.
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