Mosaic variants detectable in blood extend the clinicogenetic spectrum of GLI3-related hypothalamic hamartoma

Timothy E. Green; Mark F. Bennett; Ilka Immisch; Jeremy L. Freeman; Karl Martin Klein; John F. Kerrigan; Lata Vadlamudi; Erin L. Heinzen; Ingrid E. Scheffer; A. Simon Harvey; Felix Rosenow; Michael S. Hildebrand; Samuel F. Berkovic

Genetics in Medicine Open (Jan 2023)

Mosaic variants detectable in blood extend the clinicogenetic spectrum of GLI3-related hypothalamic hamartoma

Timothy E. Green,
Mark F. Bennett,
Ilka Immisch,
Jeremy L. Freeman,
Karl Martin Klein,
John F. Kerrigan,
Lata Vadlamudi,
Erin L. Heinzen,
Ingrid E. Scheffer,
A. Simon Harvey,
Felix Rosenow,
Michael S. Hildebrand,
Samuel F. Berkovic

Affiliations

Timothy E. Green: Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
Mark F. Bennett: Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
Ilka Immisch: Epilepsy Center Hessen and Department of Neurology, Philipps University Marburg, Marburg (Lahn), Germany
Jeremy L. Freeman: Department of Neurology, The Royal Children’s Hospital, Parkville, VIC, Australia; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, VIC, Australia
Karl Martin Klein: Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, AB, Canada; Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe University and University Hospital Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany
John F. Kerrigan: Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ
Lata Vadlamudi: University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia; Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
Erin L. Heinzen: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Department of Genetics, University of North Carolina, Chapel Hill, NC
Ingrid E. Scheffer: Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia; Department of Neurology, The Royal Children’s Hospital, Parkville, VIC, Australia; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
A. Simon Harvey: Department of Neurology, The Royal Children’s Hospital, Parkville, VIC, Australia; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, VIC, Australia
Felix Rosenow: Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe University and University Hospital Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany
Michael S. Hildebrand: Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, VIC, Australia
Samuel F. Berkovic: Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia; Correspondence and requests for materials should be addressed to Samuel F. Berkovic, Epilepsy Research Centre, Department of Medicine, University of Melbourne, 245 Burgundy St. Heidelberg, VIC 3084, Australia

Journal volume & issue: Vol. 1, no. 1
p. 100810

Abstract

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Purpose: Hypothalamic hamartoma (HH) can be syndromic (eg, Pallister-Hall syndrome [PHS], HH, and mesoaxial polydactyly) or nonsyndromic. Most PHS cases have germline variants in GLI3, but a minority remain unresolved. Some nonsyndromic HH cases have GLI3 mosaic variants in the brain. PHS and nonsyndromic HH are regarded as 2 separate GLI3-related disorders, clinically and genetically. Here, we searched for mosaic variants in unsolved cases. Methods: High-depth exome sequencing was performed on leukocyte-derived DNA in 1 unsolved PHS and 25 nonsyndromic HH cases. We searched for mosaic variants in GLI3 and other HH-associated genes. Mosaic variants were confirmed by droplet-digital polymerase chain reaction. Results: The PHS case had a GLI3 stop-gain variant c.2845G>T; p.(Glu949Ter) at 6.9% variant allele fraction (VAF). Two nonsyndromic cases had GLI3 variants—a stop-gain (c.2639C>A; p.(Ser880Ter), VAF 3.7%) and a frameshift (c.3326_3330del; p.(Glu1109AlafsTer18), VAF 7.8%). The nonsyndromic patient with 3.7% VAF in blood had 35.8% VAF in HH tissue. He had a vestigial extra digit removed adjacent to his left fifth finger. Conclusion: GLI3 mosaicism is associated with a phenotypic spectrum from PHS to HH with subtle extra PHS features, to isolated nonsyndromic HH. High-depth sequencing permits detection of low-level mosaicism, which is an important cause of both syndromic and nonsyndromic HH.

Published in Genetics in Medicine Open

ISSN: 2949-7744 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Medicine
Website: https://www.sciencedirect.com/journal/genetics-in-medicine-open

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