Mosaic variants detectable in blood extend the clinico-genetic spectrum of GLI3-related Hypothalamic Hamartoma

ICNC2024
Symposia: The Impact of Genetics In The Care of Patients With Rare Pediatric Epilepsies: Past, Present Future

Mosaic variants detectable in blood extend the clinico-genetic spectrum of GLI3-related Hypothalamic Hamartoma
Michael Hildebrand

Hypothalamic hamartoma (HH) can be syndromic (e.g. Pallister-Hall syndrome (PHS), HH and mesoaxial polydactyly) or non-syndromic. Most PHS cases have germline variants in GLI3, but a minority remain unresolved. Some non-syndromic HH cases have GLI3 mosaic variants in brain. PHS and non-syndromic HH are regarded as two separate GLI3-related disorders, clinically and genetically. Here we searched for mosaic variants in unsolved cases. High depth exome sequencing was performed on leukocyte-derived DNA in one unsolved PHS and 25 non-syndromic HH cases. We searched for mosaic variants in GLI3 and other HH associated genes. Mosaic variants were confirmed by droplet-digital PCR. The PHS case had a GLI3 stop-gain variant at 6.9% variant allele fraction (VAF). Two non-syndromic cases had GLI3 variants – a stop-gain (VAF 3.7%) and a frameshift (VAF 7.8%). One non-syndromic 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 5th finger. GLI3 mosaicism is associated with a phenotypic spectrum from PHS to HH with subtle extra PHS features, to isolated non-syndromic HH. High depth sequencing permits detection of low-level mosaicism, which is an important cause of both syndromic and non-syndromic HH.

Other Lectures in this symposium
Diagnosing Genetic Epilepsy in a Resource-Constrained Setting – the South African experience
The genetic architecture of the pediatric epilepsies
Epigenetic approaches to epilepsy diagnosis