Kagami-Ogata syndrome (upd(14)pat)

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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 DLK1MEG3 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

Molecular findings