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

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 , but a minority remain unresolved. Some nonsyndromic HH cases have mosaic variants in the brain. PHS and nonsyndromic HH are regarded as 2 separate -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 and other HH-associated genes. Mosaic variants were confirmed by droplet-digital polymerase chain reaction.

Results: The PHS case had a stop-gain variant c.2845G>T; p.(Glu949Ter) at 6.9% variant allele fraction (VAF). Two nonsyndromic cases had 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: 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.