| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Genetics in Medicine Open, Vol 1, Iss 1, Pp 100810- (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2949-7744 |
| DOI: |
10.1016/j.gimo.2023.100810 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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