Kagami Ogata syndrome: a small deletion refines critical region for imprinting

www.nature.com/npjgenmed CASE REPORT OPEN Kagami Ogata syndrome: a small deletion refines critical region for imprinting Gonench Kilich 1, Kelly Hassey1, Edward M. Behrens2, Marni Falk3, Adeline Vanderver4, Daniel J. Rader 5, Patrick J. Cahill6, Anna Raper7, Zhe Zhang8, Dawn Westerfer1, Tanaya Jadhav 9, Laura Conlin10, Kosuke Izumi10,12, Ramakrishnan Rajagopalan11,13, Kathleen E. Sullivan 1,13 ✉ and UDN Consortium* 1234567890():,; Kagami–Ogata syndrome is a rare imprinting disorder and its phenotypic overlap with multiple different etiologies hampers diagnosis. Genetic etiologies include paternal uniparental isodisomy (upd(14)pat), maternal allele deletions of differentially methylated regions (DMR) in 14q32.2 or pure primary epimutations. We report a patient with Kagami–Ogata syndrome and an atypical diagnostic odyssey with several negative standard-of-care genetic tests followed by epigenetic testing using methylation microarray and a targeted analysis of whole-genome sequencing to reveal a 203 bp deletion involving the MEG3 transcript and MEG3:TSS-DMR. Long-read sequencing enabled the simultaneous detection of the deletion, phasing, and biallelic hypermethylation of the MEG3:TSS-DMR region in a single assay. This case highlights the challenges in the sequential genetic testing paradigm, the utility of long-read sequencing as a single comprehensive diagnostic assay, and the smallest reported deletion causing Kagami–Ogata syndrome allowing important insights into the mechanism of imprinting effects at this locus. npj Genomic Medicine (2024)9:5 ; https://doi.org/10.1038/s41525-023-00389-2 INTRODUCTION Kagami–Ogata syndrome (KOS) is a rare imprinting disorder of 14q32.2 with an estimated incidence of less than 1 in 1,000,000 liveborn individuals. Over 80 cases of KOS have been reported in the literature with a characteristic phenotype including full cheeks with a protruding philtrum, increased angulation of the ribs, and developmental delay/intellectual disability1. Imprinting disorders are due to changes in the epigenetic phenomena that allow gene expression predominantly from a single parental allele2. Imprinted genes typically form a cluster with differentially methylated regions (DMRs) which regulate expression of the imprinted genes in a parent-of-origin-dependent manner. There are more than 70 imprinting-associated DMRs and each locus has unique transcriptional regulation impacted by imprinting. The human 14q32 imprinting region consists of maternally expressed non-proteincoding genes and paternally expressed protein-coding genes3,4. The maternally expressed genes (MEGs) include two long noncoding RNAs: MEG3 and MEG8. The paternally expressed genes include DLK1 and RTL1. There are two DMRs in the 14q32 imprinted region: intergenic DMR (MEG3/DLK1:IG-DMR) and MEG3:TSS-DMR in the promoter region of MEG3 (Supplemental figure). Inherited and presumed non-inherited mechanisms can cause imprinting diseases at this locus. MEG3/DLK1:IG-DMR maintains the parent-of-origin-dependent methylation patterns in the body and placenta, while MEG3:TSS-DMR does so only in the body3,4. KOS can be caused by paternal uniparental disomy of chromosome 14, maternal deletion of the 14q32.3 imprinted region, or an epimutation with hypermethylation of the DMRs5. In contrast, maternal uniparental disomy of chromosome 14, paternal deletion of the 14q32.2 imprinted region, or hypomethylation of DMRs cause Temple syndrome which has a distinct phenotype of growth failure, hypotonia, small hands and feet, broad forehead, high arched palate, and premature puberty thus resembling Prader–Willi syndrome and Silver–Russell Syndrome6. The mechanism of disease has important considerations for recurrence risk in future pregnancies. Here, we report a patient with KOS who was initially diagnosed as having Jeune syndrome and later enrolled in the Undiagnosed Disease Network (UDN). We describe her long diagnostic odyssey including a series of targeted and genome-wide genetic tests, including a negative whole-exome sequencing (WES) and wholegenome sequencing (WGS). A targeted analysis of WGS revealed a de novo 203-bp deletion of the MEG3 transcript and promoter region. Long-read sequencing of the proband enabled the simultaneous detection of the deletion, phasing of the de novo variant, and the methylation status of the MEG3:TSS-DMR locus. The deletion impacts MEG3 expression and demonstrates that loss of MEG3 transcription from the maternal allele leads to hypermethylation of MEG3/DLK1:IG-DMR and MEG3:TSS-DMR. This 1 Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 2Division of Rheumatology, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. 3Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 4Division of Neurology, Children’s Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5Departments of Medicine, Pediatrics and Genetics, Perelman School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 6Division of Orthopedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 7Division of Translational Medicine and Human Genetics, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. 8The Center for Biomedical Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 9Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 10Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 11 Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 12Present address: Division of Genetics and Metabolism, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA. 13These authors contributed equally: Ramakrishnan Rajagopalan, Kathleen E. Sullivan. A list of members and their affiliations appears in the Supplementary Information. ✉email: Published in partnership with CEGMR, King Abdulaziz University G. Kilich et al. 1234567890():,; 2 Fig. 1 Clinical features of the patient. A Shortly after birth, the “coat hanger” rib deformities are seen. B Supine view demonstrating the impact of her rib cage and scoliosis on her abdominal content. C A seated view of the impact of the rib cage and scoliosis on her abdominal contents. D The acetabular dysplasia is seen on this view and the progress (...truncated)