Clinical characteristics.

Kagami-Ogata syndrome is characterized by developmental delay, intellectual disability, feeding difficulty with impaired swallowing, full cheeks, prominent and deep philtrum, small bell-shaped thorax with coat-hanger appearance of the ribs, and abdominal wall defects (omphalocele and diastasis recti). Additional common features include joint contractures, kyphoscoliosis, coxa valga, and laryngomalacia. Cardiac disease and hepatoblastoma have also been reported.

Diagnosis/testing.

The diagnosis of Kagami-Ogata syndrome is established in a proband with suggestive findings and findings on molecular genetic testing that suggest deficient expression of the RTL1 antisense (RTL1as) allele of maternal origin due to one of the following: paternal uniparental disomy of chromosome 14; epimutation (hypermethylation) affecting the normally unmethylated MEG3/DLK1 intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and MEG3 transcription start site DMR (MEG3:TSS-DMR) on the maternal allele; deletion of the maternally inherited 14q32.2 region that includes MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR, and may include RTL1as; deletion of the maternally inherited RTL1as but not MEG3/DLK1:IG-DMR or MEG3:TSS-DMR; translocation (or inversion) disrupting the integrity between the maternally inherited MEG3 promoter at the MEG3:TSS-DMR and RTL1as.

Management.

Treatment of manifestations: Developmental and educational support; mechanical ventilation and oxygen therapy as needed after birth; tracheostomy as required; monitor and treat upper and lower respiratory tract infections; treatment of scoliosis per orthopedist; treatment of joint contractures per rehabilitation medicine specialist; tube feeding typically required for poor weight gain; gastrostomy tube feeding as needed; feeding training; treatment of cardiac disease per cardiologist; standard treatment of hepatoblastoma with surgery and chemotherapy; social work and family support.

Surveillance: Monitor developmental progress, educational needs, for evidence of aspiration or respiratory insufficiency, progression of kyphoscoliosis and joint contractures, nutritional status, safety of oral intake, constipation, and family and care coordination needs at each visit. Echocardiogram annually; abdominal ultrasound and serum alpha-fetoprotein every three months until age three to four years.

Agents/circumstances to avoid: Avoid exposure to respiratory infections; individuals with Kagami-Ogata syndrome may develop respiratory failure with respiratory infections, especially during infancy.

Genetic counseling.

The recurrence risk of Kagami-Ogata syndrome is dependent on the genetic mechanism underlying deficient expression of the maternal RTL1as allele in the proband. In most affected individuals, the underlying genetic mechanism occurs as a de novo event and the recurrence risk to sibs is not increased. Less commonly, a parent of a proband has a predisposing genetic alteration associated with an increased recurrence risk to sibs. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions. If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing and preimplantation genetic testing are possible. Methylation testing of fetal DNA to examine abnormal methylation patterns of the DMRs (MEG3/DLK1:IG-DMR and MEG3:TSS-DMR) is not recommended; while DNA extracted from amniotic fluid is currently believed to provide the most reliable tissue source for evaluating fetal methylation status, false negative findings have been reported.

Suggestive Findings

Kagami-Ogata syndrome should be suspected in individuals with the following clinical findings, especially specific (pathognomonic) findings in addition to characteristic but not specific findings and nonspecific findings [Kagami et al 2015, Ogata & Kagami 2016].

Specific (pathognomonic) findings

• Full cheeks and prominent and deep philtrum (See Figure 1.)
• Small bell-shaped thorax with coat-hanger appearance of the ribs (See Figure 2.)
  Note: Coat-hanger angle is increased from mid-gestation through childhood. Mid-to-widest thorax ratio is decreased from birth through early childhood [Miyazaki et al 2011, Kagami et al 2015, Ogata & Kagami 2016, Kuriki et al 2022].

Figure 1.

Female at infancy, age two years, and age eight years with Kagami-Ogata syndrome due to a maternally inherited microdeletion of DLK1, MEG3/DLK1:IG-DMR, MEG3:TSS-DMR, MEG3, RTL1/RTL1as, MEG8, and a centromeric part of the snoRNA genes. Characteristic full (more...)

Figure 2.

Chest radiograph of a Japanese neonate with Kagami-Ogata syndrome. The coat-hanger angle (CHA) is increased from 30 weeks' gestation through age five years in individuals with Kagami-Ogata syndrome. CHA is the average of the right and left angles between (more...)

Characteristic but not specific findings

• Abdominal wall defects such as omphalocele and diastasis recti
• Placentomegaly
• Polyhydramnios

Nonspecific findings

• Craniofaciocervical features such as frontal bossing, hirsute forehead, blepharophimosis, depressed nasal bridge, anteverted nares, puckered lips, micrognathia, and short, webbed neck
• Relatively large birth weight
• Developmental delay (moderate to severe)
• Feeding difficulty with impaired swallowing
• Joint contractures
• Kyphoscoliosis

Note: Characteristic face, small bell-shaped thorax with coat-hanger appearance of the ribs, and omphalocele can be observed on fetal ultrasound and MRI from the second trimester [Chen et al 2019, Igreja da Silva et al 2019, Molinet Coll et al 2021, Kuriki et al 2022].

Establishing the Diagnosis

The diagnosis of Kagami-Ogata syndrome is established in a proband with suggestive findings and findings on molecular genetic testing that suggest deficient expression of the RTL1 antisense (RTL1as) allele of maternal origin due to one of the following (see Table 1):

• Paternal uniparental disomy of chromosome 14 (upd(14)pat) (~50% of affected individuals)
• Epimutation (hypermethylation) affecting the normally unmethylated MEG3/DLK1 intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and MEG3 transcription start site DMR (MEG3:TSS-DMR) of maternal origin (~25% of affected individuals)
• Deletion of the maternally inherited 14q32.2 region that includes MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR, and may include RTL1as (~20% of affected individuals)
• Deletion of the maternally inherited RTL1as but not MEG3/DLK1:IG-DMR or MEG3:TSS-DMR (~5% of affected individuals)
• Translocation (or inversion) disrupting the integrity between the maternally inherited MEG3 promoter at the MEG3:TSS-DMR and RTL1as (rare)

Molecular genetic testing for Kagami-Ogata syndrome includes recommended first-tier testing (methylation-specific multiple ligation-dependent probe amplification [MS-MLPA]) and second-tier testing (parent-of-origin analysis for chromosome 14) as needed to identify the molecular cause and clarify recurrence risk (see Figure 3).

Figure 3.

Testing algorithm to establish the diagnosis and molecular cause of Kagami-Ogata syndrome Chr. = chromosome; DMR = differentially methylated region; KOS14 = Kagami-Ogata syndrome; MS-MLPA = methylation-specific multiple ligation-dependent probe amplification; (more...)

Clinical Description

Kagami-Ogata syndrome is characterized by developmental delay, intellectual disability, feeding difficulty, full cheeks and prominent and deep philtrum, small bell-shaped thorax with coat-hanger appearance of the ribs, and abdominal wall defects (omphalocele and diastasis recti). Additional common features include joint contractures, kyphoscoliosis, coxa valga, and laryngomalacia. Cardiac disease and hepatoblastoma have also been reported [Kagami et al 2015, Ogata & Kagami 2016]. To date, approximately 100 individuals have been diagnosed with Kagami-Ogata syndrome [Sakaria et al 2021; Mackay et al 2022; Smith et al 2024; T Ogata & M Kagami, unpublished observations].

Pregnancy and delivery. Polyhydramnios is typically identified in the second trimester at a median gestational age of 25.5 weeks (range: 14-30 weeks' gestation); amnioreduction is required in most pregnancies after 25 weeks' gestation (~80%) and in almost all pregnancies after 30 weeks' gestation. Polyhydramnios is due to placentomegaly and impaired swallowing. Thoracic and abdominal abnormalities are found on prenatal ultrasound in ~40% of fetuses from approximately 25 weeks' gestation. Premature delivery is frequent (~80%), with a median gestational age at delivery of 32.5 weeks (range: 30-35 weeks' gestation).

Developmental delay. Head control occurs at a median age of seven months (range: 3-36 months). Sitting without support occurs at a median age of 12 months (range: 8-25 months). Walking without support occurs at a median age of 25.5 months (range: 20-49 months). Only mild delay has been reported in two individuals with Kagami-Ogata syndrome: one individual with an epimutation [Higashiyama et al 2022] and one with mosaic paternal uniparental disomy of chromosome 14 (upd(14)pat) [Haug et al 2017].

Intellectual disability. Intellectual disability is reported in all individuals, with a median IQ of 55 (range: 29-70).

No abnormal brain MRI findings were delineated in five individuals examined.

Growth. Prenatal growth is well preserved and birth weight and length are usually above the mean. Range in birth weight is 0.1 standard deviations (SD) below the mean to 8.8 SD above the mean, and range in birth length is 1.7 SD below the mean to 3.0 SD above the mean. However, postnatal growth is frequently compromised primarily due to poor nutrition related to respiratory failure and feeding difficulty. In individuals age one to 15 years, range in weight is 6.0 SD below the mean to 4.0 SD above the mean, and range in length/height is 8.7 SD below the mean to 1.1 SD above the mean.

Craniofacial features (see Figure 1) in individuals with Kagami-Ogata syndrome include frontal bossing (~75%), hirsute forehead (~70%), blepharophimosis (70%-75%), full cheeks (>90%), depressed nasal bridge (>90%), anteverted nares (80%), prominent and deep philtrum (>95%), puckered (somewhat narrow and tented) lips (>50%), micrognathia (~100%), and short, webbed neck (>90%). Craniofacial features are typically present in infancy and consistently recognizable during childhood. While many of the craniofacial features are nonspecific, full cheeks and prominent and deep philtrum are very common and appear specific to Kagami-Ogata syndrome.

Thoracic abnormalities with respiratory failure. A small bell-shaped thorax is evident in infancy. Objective assessment of increased coat-hanger angle and decreased mid-to-widest thorax ratio is possible from fetal life through childhood (see Figure 2). The shape of the thorax appears normal after infancy, whereas coat-hanger appearance of the ribs remains discernible throughout childhood. Because of the thoracic anomalies, mechanical ventilation with oxygen has been required in more than 90% of individuals, with a median duration of one month (range: 0.1-17 months). Tracheostomy is sometimes necessary due to severe laryngomalacia.

Other skeletal abnormalities. Contractures at various joints, kyphoscoliosis, and coxa valga are also reported. The severity of these findings is variable among affected individuals.

Feeding/gastrointestinal manifestations. Tube feeding was required in all individuals who survived more than one week, with a median duration of 7.5 months (range: 0.1-89 months). Diastasis recti is common, and omphalocele can also occur. Abdominal wall weakness may cause constipation.

Cardiac disease. Cardiovascular malformations are recognized in ~25% of affected individuals. Of eight individuals who have been confirmed to have cardiac malformations, two have atrial septal defect, one has ventricular septal defect, four have patent ductus arteriosus, and one has pulmonary stenosis. These cardiac lesions are mild and do not require intensive medication or surgery. No individuals have been reported to have cardiomyopathy or conduction defects.

Hepatoblastoma has been identified in three individuals during infancy out of the 100 reported individuals to date.

Other. Simple seizure was reported in one individual [Kagami et al 2015].

Prognosis. Mortality is relatively high before age five years (20%-25% of individuals), but increased mortality is not observed in those with Kagami-Ogata syndrome older than age five years. The cause of death is variable; respiratory failure constitutes the primary cause of death. To date, nine adults age 18 years and older with Kagami-Ogata syndrome have been identified, including four unpublished individuals; the oldest affected individual is age 35 years [Smith et al 2024; T Ogata & M Kagami, personal observations].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been identified [Kagami et al 2015].

Note: Paternal uniparental disomy of chromosome 14, epimutations, and deletions that do not include RTL1as are associated with approximately five times the RTL1 expression compared to controls, whereas deletions including RTL1as are associated with approximately 2.5 times the RTL1 expression (see Molecular Genetics). However, because of the small number of deletions including RTL1as, it is unknown if the phenotype is milder in individuals with approximately 2.5 times the RTL1 expression than in individuals with five times the RTL1 expression compared to controls.

Penetrance

Penetrance is complete, and affected individuals invariably show full cheeks, prominent and deep philtrum, and small bell-shaped thorax with coat-hanger appearance of the ribs. However, there could be bias in that molecular studies are performed only when individuals have certain clinical features. In this regard, two individuals with upd(14)pat mosaicism have been reported to date; one individual has a mild phenotype, while the other has a typical Kagami-Ogata syndrome phenotype [Haug et al 2017, Li et al 2021]. Thus, some mosaic individuals with nearly normal phenotype may have been overlooked.

Nomenclature

Kagami-Ogata syndrome has also been referred to as upd(14)pat syndrome. However, the term upd(14)pat syndrome may be misleading, as Kagami-Ogata syndrome can be caused by genetic mechanisms other than paternal uniparental disomy of chromosome 14. Thus, "Kagami-Ogata syndrome" has been proposed to describe the unique clinical entity caused by various (epi)genetic aberrations affecting the chromosome 14q32.2 imprinted region.

Prevalence

To date, approximately 100 individuals with Kagami-Ogata syndrome have been reported [Mackay et al 2022, Eggermann et al 2023]. In Japan, 76 individuals with Kagami-Ogata syndrome (some of whom are reported in the literature) have been identified [T Ogata & M Kagami, personal observations]. It is likely that many individuals remain undiagnosed.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Kagami-Ogata syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Avoid exposure to respiratory infections; individuals with Kagami-Ogata syndrome may develop respiratory failure with respiratory infections, especially during infancy.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

The recurrence risk of Kagami-Ogata syndrome is dependent on the genetic mechanism underlying deficient expression of the maternal RTL1as allele in the proband. Genetic mechanisms known to be causative of Kagami-Ogata syndrome include the following:

• Paternal uniparental disomy of chromosome 14 (upd(14)pat) *
• Epimutation (hypermethylation) of the normally unmethylated MEG3/DLK1 intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and MEG3 transcription start site DMR (MEG3:TSS-DMR) of maternal origin *
• Deletion of the 14q32.2 region that includes MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR, and may include RTL1as *
• Translocation (or inversion) disrupting the integrity between the maternally inherited MEG3 promoter at the MEG3:TSS-DMR and RTL1as

In most affected individuals, the underlying genetic mechanism occurs as a de novo event and the recurrence risk to sibs is not increased. Less commonly, a parent of the proband has a predisposing genetic alteration (e.g., a maternally transmitted deletion) associated with an increased recurrence risk to sibs.

* If the diagnosis of Kagami-Ogata syndrome in the proband has been established by identification of hypermethylation of MEG3/DLK1:IG-DMR and MEG3:TSS-DMR, deletion analysis (if not already performed in conjunction with methylation analysis via MS-MLPA) and parent-of-origin analysis are required to distinguish upd(14)pat, epimutation, and deletions involving the DMRs. Parent-of-origin analysis for chromosome 14 using polymorphic DNA markers (which requires a DNA sample from the proband and both parents) can distinguish upd(14)pat and biparental chromosome 14 suggesting an epimutation (see Establishing the Diagnosis and Figure 3).

Risk to Family Members

Parents of a proband

• The parents of a proband with Kagami-Ogata syndrome are not affected with Kagami-Ogata syndrome but may have a predisposing genetic alteration associated with the disorder such the following:
  • Maternal deletion involving the DMRs (MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR) and, in some individuals, RTL1as. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [Kagami et al 2008, Beygo et al 2015, Kagami et al 2015, Luk 2017].
    If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves DLK1 (deletion of DLK1 is a disease-causing factor for Temple syndrome but not for Kagami-Ogata syndrome) (see Genetically Related Disorders).
    Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [Kagami et al 2008]. Transmission of a deletion from a mother with Kagami-Ogata syndrome to a child with Kagami-Ogata syndrome has not been reported to date.
  • Maternal translocation (or inversion) disrupting the integrity between the MEG3 promoter and RTL1as
  • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)).
• Evaluation of the parents to clarify recurrence risk is recommended; specific testing recommendations depend on the genetic mechanism underlying Kagami-Ogata syndrome in the proband (see Sibs of a proband).

Sibs of a proband. The risk to sibs depends on the underlying genetic mechanism in the proband and the genetic status of the parents. If the genetic mechanism underlying Kagami-Ogata syndrome in the proband is:

• Paternal uniparental disomy of chromosome 14. If the genetic mechanism underlying Kagami-Ogata syndrome in the proband is upd(14)pat, karyotype of the proband is recommended to identify those with a robertsonian translocation or i(14q) [Ogata & Kagami 2016]. If a robertsonian translocation or i(14q) is identified in the proband (or if the chromosomal status of the proband is unknown), parental karyotyping is recommended.
  • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a de novo event and the recurrence risk to sibs is <1%.
  • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [Wang et al 2020], sib recurrence of upd(14)pat mediated by this mechanism has not been reported.
• Epimutation (hypermethylation) of the maternally inherited DMRs. If the genetic mechanism underlying Kagami-Ogata syndrome in the proband is epimutation (hypermethylation) of the maternally inherited DMRs, it is presumed that hypermethylation occurred in the proband as a de novo event and the recurrence risk to sibs is <1%. Additional testing of the proband and the parents is not required to clarify recurrence risk. Note: (1) The underlying genetic mechanism of hypermethylation is unknown. (2) Kagami-Ogata syndrome associated with multilocus imprinting disturbance (MLID) has not been reported [Kagami et al 2017a].
• Deletion involving the maternally inherited 14q32.2 imprinted region. If the genetic mechanism underlying Kagami-Ogata syndrome in the proband is deletion involving the maternally inherited 14q32.2 imprinted region, targeted deletion analysis is recommended for the mother of the proband.
  • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a de novo event and the recurrence risk to sibs is <1%. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only. (Gonadal mosaicism for a deletion involving the 14q32.2 imprinted region has not been reported to date.)
  • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [Kagami et al 2008, Beygo et al 2015, Kagami et al 2015, Luk 2017]. (Note: If the deletion includes DLK1 and the mother inherited the deletion from her father, the mother likely has Temple syndrome.)
• Translocation or inversion disrupting the integrity between the maternally inherited MEG3 promoter and RTL1as. If the genetic mechanism underlying Kagami-Ogata syndrome in the proband is translocation or inversion disrupting the integrity between the maternally inherited MEG3 promoter and RTL1as, karyotype analysis is recommended for the mother of the proband.
  • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a de novo event and the recurrence risk to sibs is <1%.
  • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased.

Offspring of a proband. Many individuals with Kagami-Ogata syndrome are not yet of reproductive age and, to date, individuals with Kagami-Ogata syndrome are not known to reproduce. However, reproductive function is predicted to be preserved in Kagami-Ogata syndrome and the following recurrence risk issues should be considered:

• If the proband has a deletion involving the 14q32.2 imprinted region, offspring of the proband are at risk for Kagami-Ogata syndrome or Temple syndrome depending on the sex of the proband and the deletion size. If the proband is a female, offspring are predicted to have a 50% risk of Kagami-Ogata syndrome. If the proband is male and the deletion encompasses DLK1, offspring are predicted to have a 50% risk of Temple syndrome.
• If the proband has a chromosome alteration predicted to result in uniparental disomy in offspring (e.g., a robertsonian translocation or isochromosome 14q), offspring of the proband are at risk for upd(14)pat-mediated Kagami-Ogata syndrome or upd(14)mat-mediated Temple syndrome, depending on the sex of the proband and the underlying mechanism for the development of uniparental disomy (i.e., trisomy rescue or monosomy rescue).

Other family members

• If the mother of the proband is heterozygous for a deletion involving the 14q32.2 imprinted region, the mother's sibs are at risk of having the deletion.
• If a chromosome alteration involving 14q32.2 (e.g., a translocation) is identified in the mother of the proband, the mother's sibs are at risk of having the chromosome alteration.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular Pathogenesis

The primary underlying factor for the development of Kagami-Ogata syndrome is increased (~2.5 times or ~5 times that of controls) RTL1 expression due to absence of the functional RTL1 antisense (RTL1as) allele of maternal origin that acts as a trans-acting repressor for RTL1 expression [Kagami et al 2015, Ogata & Kagami 2016]. The maternal 14q32.2 region normally includes unmethylated MEG3/DLK1 intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and unmethylated MEG3 transcription start site DMR (MEG3:TSS-DMR), resulting in normal expression of RTL1as. RTL1as expressed from the maternal allele represses RTL1 expression on the paternal allele (see Figure 4A).

Figure 4.

Chromosome 14q32.2 imprinted region and representative genetic causes leading to Kagami-Ogata syndrome. The black and white circles represent methylated and unmethylated differentially methylated regions (DMRs), respectively. A. Structure and character (more...)

Structure and character of the 14q32.2 imprinted region

• This imprinted region contains the germline-derived MEG3/DLK1:IG-DMR and the postfertilization-derived MEG3:TSS-DMR; the protein-coding paternally expressed genes DLK1 and RTL1; and the non-coding maternally expressed genes MEG3, RTL1as, MEG8, and snoRNA and microRNA genes (see Figure 4A).
• Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission in the body; in the placenta, the MEG3/DLK1:IG-DMR remains as a DMR, but the MEG3:TSS-DMR is grossly hypomethylated regardless of parental origin.
• The unmethylated MEG3:TSS-DMR and the MEG3/DLK1:IG-DMR of maternal origin function as imprinting control centers in the body and the placenta, respectively, and the MEG3:TSS-DMR can remain unmethylated only in the presence of unmethylated MEG3/DLK1:IG-DMR, because of the hierarchical regulation of the methylation patterns between the two DMRs [Kagami et al 2010].
• All the non-coding maternally expressed genes are part of a large transcript expressed by the MEG3 promoter.

Mechanisms of disease causation include paternal uniparental disomy of chromosome 14 (upd(14)pat), epimutation (hypermethylation) of MEG3/DLK1:IG-DMR and MEG3:TSS-DMR of maternal origin, deletion of MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR of maternal origin, deletion of the maternally inherited RTL1as, or translocation (or inversion) disrupting the integrity between the maternally inherited MEG3 promoter at the MEG3:TSS-DMR and RTL1as.

Paternal uniparental disomy of chromosome 14. Advanced maternal age at childbirth is a risk factor for the development of monosomy rescue-mediated upd(14)pat [Kagami et al 2012].

Epimutation (hypermethylation) of the normally unmethylated MEG3/DLK1:IG-DMR and MEG3:TSS-DMR of maternal origin causes absence of functional RTL1as and results in a paternal methylation pattern.

• Abnormal methylation of MEG3/DLK1:IG-DMR leads to abnormal methylation of MEG3:TSS-DMR on the maternally derived allele. There is no report describing hypermethylation of MEG3/DLK1:IG-DMR alone or MEG3:TSS-DMR alone.
• The underlying cause of hypermethylation is unknown, and no multilocus imprinting disturbance (MLID) has been identified in individuals with Kagami-Ogata syndrome [Kagami et al 2017a].

Deletions including either DMRs

• Deletions of MEG3/DLK1:IG-DMR and/or MEG3:TSS-DMR of maternal origin cause absence of functional RTL1as and a paternal methylation pattern [Kagami et al 2010].
• Three different deletions involving maternally inherited MEG3:TSS-DMR alone have caused a paternal methylation pattern [Kagami et al 2010, Beygo et al 2015, Kilich et al 2024].
• DMR deletions that include RTL1as result in ~2.5 times RTL1 expression compared to that of controls; DMR deletions that do not include RTL1as result in about five times RTL1 expression in the absence of functional RTL1as.
• When deletions include DLK1, this leads to normal DLK1 expression, whereas when they do not include DLK1, this results in around two times the DLK1 expression seen in controls.
• MEG genes are deleted or silenced.

Deletion of RTL1as (not including MEG3/DLK1:IG-DMR or MEG3:TSS-DMR)

• This deletion results in loss of RTL1as expression from the maternally inherited chromosome 14q32.2 and resultant overexpression of RTL1 without altered methylation.
• MEG8 is also deleted or disrupted in all deletions of this type reported to date.
• DLK1 and non-deleted maternally expressed genes are predicted to be expressed normally.

Translocation disrupting the integrity between the MEG3 promoter and RTL1as silences transcription of RTL1as.

Author Notes

Tsutomu Ogata (pj.ca.dem-amah@atagomot) and Masayo Kagami (pj.og.dhccn@sm-imagak) are actively involved in clinical research regarding individuals with Kagami-Ogata syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of Kagami-Ogata syndrome or other considerations.

National Research Institute for Child Health and Development

European Network for Human Congenital Imprinting Disorders

Acknowledgments

This work was supported by the grant from Japan Agency for Medical Research and Development (AMED) (24ek0109587).

Revision History

• 24 October 2024 (sw) Review posted live
• 29 February 2024 (to) Original submission

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