BACKGROUND: Kagami-Ogata syndrome (KOS) and Temple syndrome (TS) are two imprinting disorders characterized by the absence or reduced expression of maternal or paternal genes in the chromosome 14q32 region, respectively. We present a rare prenatally diagnosed case of recurrent KOS inherited from a mother affected by TS.
METHODS: The woman\'s two affected pregnancies exhibited recurrent manifestations of prenatal overgrowth, polyhydramnios, and omphalocele, as well as a small bell-shaped thorax with coat-hanger ribs postnatally. Prenatal genetic testing using a single-nucleotide polymorphism array detected a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother, leading to the diagnosis of KOS. Additionally, the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region and presented with short stature and small hands and feet, indicating a diagnosis of TS.
CONCLUSIONS: Given the rarity of KOS as an imprinting disorder, accurate prenatal diagnosis of this rare imprinting disorder depends on two factors: (1) increasing clinician recognition of the clinical phenotype and related genetic mechanism, and (2) emphasizing the importance of imprinted regions in the CMA workflow for laboratory analysis.

Uniparental disomy (UPD)-related imprinting disorders are a group of congenital disorders which can lead to severe birth defects. Their molecular etiology is the occurrence of UPD in the genomic imprinting regions, which may cause disturbed expression of parent-of-origin imprinted genes. With the widespread applications of genetic testing techniques, the prenatal diagnosis of UPD-related imprinted diseases has gradually become clinical routines. However, due to the complicated pathogenesis of such disorders, currently there is still a lack of standards and norms for the understanding, diagnosis, management and genetic counseling. By referring to the relevant guidelines and consensus, the latest progress of research, and opinions from experts in the relevant fields, the writing group has formulated a consensus over the prenatal diagnosis and genetic counseling for UPD-related imprinting disorders, with an aim to provide a more accurate and rational evaluation in prenatal clinics.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

With the increasing maturity and widespread application of assisted reproductive technology (ART), more attention has been paid to the health outcomes of offspring following ART. It is well established that children born from ART treatment are at an increased risk of imprinting errors and imprinting disorders. The disturbances of genetic imprinting are attributed to the overlap of ART procedures and important epigenetic reprogramming events during the development of gametes and early embryos, but the detailed mechanisms are hitherto obscure. In this review, we summarized the DNA methylation-dependent and independent mechanisms that control the dynamic epigenetic regulation of imprinted genes throughout the life cycle of a mammal, including erasure, establishment, and maintenance. In addition, we systematically described the dysregulation of imprinted genes in embryos conceived through ART and discussed the corresponding underlying mechanisms according to findings in animal models. This work is conducive to evaluating and improving the safety of ART.

Genomic imprinting is a term used for an intergenerational epigenetic inheritance and involves a subset of genes expressed in a parent-of-origin-dependent way. Imprinted genes are expressed preferentially from either the paternally or maternally inherited allele. Long non-coding RNAs play essential roles in regulating this allele-specific expression. In several well-studied imprinting clusters, long non-coding RNAs have been found to be essential in regulating temporal- and spatial-specific establishment and maintenance of imprinting patterns. Furthermore, recent insights into the epigenetic pathological mechanisms underlying human genomic imprinting disorders suggest that allele-specific expressed imprinted long non-coding RNAs serve as an upstream regulator of the expression of other protein-coding or non-coding imprinted genes in the same cluster. Aberrantly expressed long non-coding RNAs result in bi-allelic expression or silencing of neighboring imprinted genes. Here, we review the emerging roles of long non-coding RNAs in regulating the expression of imprinted genes, especially in human imprinting disorders, and discuss three strategies targeting the central long non-coding RNA UBE3A-ATS for the purpose of developing therapies for the imprinting disorders Prader-Willi syndrome and Angelman syndrome. In summary, a better understanding of long non-coding RNA-related mechanisms is key to the development of potential therapeutic targets for human imprinting disorders.

Recurrent hydatidiform moles (RHMs) are human pregnancies with abnormal embryonic development and hyperproliferating trophoblast. Biallelic mutations in NLRP7 and KHDC3L, members of the subcortical maternal complex (SCMC), explain the etiology of RHMs in only 60% of patients. Here we report the identification of seven functional variants in a recessive state in three SCMC members, five in NLRP7, one in NLRP5, and one in PADI6. In NLRP5, we report the first patient with RHMs and biallelic mutations. In PADI6, the patient had four molar pregnancies, two of which had fetuses with various abnormalities including placental mesenchymal dysplasia and intra-uterine growth restriction, which are features of Beckwith-Wiedemann syndrome and Silver Russell syndrome, respectively. Our findings corroborate recent studies and highlight the common oocyte origin of all these conditions and the continuous spectrum of abnormalities associated with deficiencies in the SCMC genes.

Kagami-Ogata syndrome (KOS) is a rare imprinting disorder characterized by skeletal abnormalities, dysmorphic facial features, growth retardation and developmental delay. The genetic etiology of KOS includes paternal uniparental disomy 14 [upd(14)pat], epimutations and microdeletions affecting the maternally derived imprinted region of chromosome 14q32.2. More than seventy KOS cases have been reported thus far; however, only 10, including two familial, are associated with upd(14)pat harboring Robertsonian translocation (ROB). Here, we reported a male infant with clinical manifestations of facial dysmorphism, bell-shaped small thorax, and omphalocele. Karyotype analyses identify a balanced ROB involving the long arms of chromosomes 13 and 14 both in the patient and his father. We further confirm the pattern of upd(14)pat utilizing DNA polymorphic markers. In conclusion, our case report provides a new male KOS case caused by upd(14)pat with paternally inherited Robertsonian translocation, which represents the second male case officially reported. Notably, a KOS case due to upd(14)pat and ROB is rare. An accurate diagnosis requires not only the identification of the characteristic clinical features but also systemic cytogenetic and molecular studies.