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

Gonench Kilich; Kelly Hassey; Edward M Behrens; Marni Falk; Adeline Vanderver; Daniel J Rader; Patrick J Cahill; Anna Raper; Zhe Zhang; Dawn Westerfer; Tanaya Jadhav; Laura Conlin; Kosuke Izumi; Ramakrishnan Rajagopalan; Kathleen E Sullivan; UDN Consortium

doi:10.1038/s41525-023-00389-2

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

NPJ Genom Med. 2024 Jan 11;9(1):5. doi: 10.1038/s41525-023-00389-2.

Authors

Gonench Kilich¹, Kelly Hassey¹, Edward M Behrens², Marni Falk³, Adeline Vanderver⁴, Daniel J Rader⁵, Patrick J Cahill⁶, Anna Raper⁷, Zhe Zhang⁸, Dawn Westerfer¹, Tanaya Jadhav⁹, Laura Conlin¹⁰, Kosuke Izumi^{10

11}, Ramakrishnan Rajagopalan^#¹², Kathleen E Sullivan^#¹³; UDN Consortium

Affiliations

¹ Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
² Division of Rheumatology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
³ Mitochondrial 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.
⁴ Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Departments of Medicine, Pediatrics and Genetics, Perelman School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶ Division of Orthopedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Division of Translational Medicine and Human Genetics, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
⁸ The Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Division of Genetics and Metabolism, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA.
¹² 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.
¹³ Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. sullivank@chop.edu.

^# Contributed equally.

Abstract

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.

Abstract

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