Kagami-Ogata syndrome: a clinically recognizable upd(14)pat and related disorder affecting the chromosome 14q32.2 imprinted region

Abstract

Human chromosome 14q32.2 carries paternally expressed genes including DLK1 and RTL1, and maternally expressed genes including MEG3 and RTL1as, along with the germline-derived DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived MEG3-DMR. Consistent with this, paternal uniparental disomy 14 (upd(14)pat), and epimutations (hypermethylations) and microdeletions affecting the IG-DMR and/or the MEG3-DMR of maternal origin, result in a unique phenotype associated with characteristic face, a small bell-shaped thorax with coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly and polyhydramnios. Recently, the name 'Kagami-Ogata syndrome' (KOS) has been approved for this clinically recognizable disorder. Here, we review the current knowledge about KOS. Important findings include the following: (1) the facial 'gestalt' and the increased coat-hanger angle constitute pathognomonic features from infancy through childhood/puberty; (2) the unmethylated IG-DMR and MEG3-DMR of maternal origin function as the imprinting control centers in the placenta and body respectively, with a hierarchical interaction regulated by the IG-DMR for the methylation pattern of the MEG3-DMR in the body; (3) RTL1 expression level becomes ~2.5 times increased in the absence of functional RTL1as-encoded microRNAs that act as a trans-acting repressor for RTL1; (4) excessive RTL1 expression and absent MEG expression constitute the primary underlying factor for the phenotypic development; and (5) upd(14)pat accounts for approximately two-thirds of KOS patients, and epimutations and microdeletions are identified with a similar frequency. Furthermore, we refer to diagnostic and therapeutic implications.

Figure 1

Unique pathognomonic features in Kagami–Ogata syndrome (KOS). (a) Photographs of a patient with a maternally inherited 411 354 bp microdeletion involving DLK1, the IG-DMR, the MEG3-DMR, MEG3, RTL1/RTL1as, MEG8 and a centromeric part of snoRNAs (Deletion-4 in Figure 3). IG-DMR, intergenic differentially methylated region. The facial ‘gestalt' with full cheeks and protruding philtrum is observed from infancy through childhood. (b) Chest roentgenogram of a hitherto unreported Japanese neonatal patient with an epimutation. The CHA (coat-hanger angle) to the ribs is increased, and the M/W ratio (the ratio of the mid to widest thorax diameter) is decreased. Normal values are based on our previous report.

Figure 2

The human chromosome 14q32.2 imprinted region. (a) Schematic representation of the physical map of this region. PEGs are shown in blue, MEGs in red, a probably non-imprinted gene (DIO3) in black and the DMRs in green. (b) Methylation patterns of the DMRs. Black, white and gray painted circles represent methylated DMRs, unmethylated DMRs and non-DMRs, respectively. The arrow indicates a hierarchical interaction between the IG-DMR and the MEG3-DMR that appears to be medicated by cis-acting ncRNAs (the IG-DMR RNA) that exerts an enhancer-like function for the MEG3 promoter and prevents the MEG3-DMR from methylation. The deleted regions are shown with stippled squares. (c) Interaction between RTL1 and RTL1as. In control subjects, RTL1as-encoded microRNAs function as a trans-acting repressor for RTL1. In upd(14)pat patients, RTL1 expression level becomes ~5 times increased because of two copies of functional RTL1 and no functional RTL1as (shown with thick arrows). DMR, differentially methylated region; ICC, imprinting control center; IG-DMR, intergenic differentially methylated region; M, maternally derived chromosome; MEGs, maternally expressed genes; ncRNA, noncoding RNA; P, paternally derived chromosome; PEGs, paternally expressed genes; upd(14)pat, paternal uniparental disomy 14.

Figure 3

Expression patterns of the imprinted genes and methylation patterns (modified from our previous report). For explanations, see the legend for Figure 2. MEG3 is not expressed in Deletions-6–7, because MEG3 exons 1–3 are deleted.

Figure 4

Schematic representation of the generation of upd(14)pat in patients or parents with Robertsonian translocation or i(14q). MR, monosomy rescue; TR, trisomy rescue; upd(14)pat, paternal uniparental disomy 14. (a) Hetero-upd(14)pat mediated by paternal Robertsonian translocation and post-zygotic TR. (b) Iso-upd(14)pat mediated by maternal Robertsonian translocation and post-zygotic MR. (c) Iso-upd(14)pat generated by concomitant occurrence of post-zygotic MR and isochromosome formation. (d) Iso-upd(14)pat generated by sequential occurrence of meiotic isochromosome formation and post-zygotic TR. (e) Iso-upd(14)pat generated by sequential occurrence of mitotic isochromosome formation and TR.

Figure 5

Molecular diagnostic flowchart. Methylation analysis is performed by combined bisulfite restriction analysis, bisulfite sequencing, multiple ligation probe amplification (MLPA) using SALSA MLPA kit ME032 UPD7/UPD14 (MRC-Holland, Amsterdam, The Netherlands) or pyrosequencing. Parent-of-origin analysis is carried out by microsatellite analysis or single-nucleotide polymorphism (SNP) array. Deletion analysis is performed by MLPA, fluorescence in situ hybridization or array comparative genomic hybridization. Methylation and deletion analyses need DNA samples of patients alone, whereas parent-of-origin analysis requires DNA samples of patients and their parents. MLPA is utilized for deletion analysis and methylation analysis before and after digestion of the genomic DNA samples with a methylation-sensitive restriction enzyme HhaI, respectively.