Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma

Objective Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH).

Methods Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples.

Results We identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3–p21.31 and 2 somatic cnLOH; one at 11q12.2–q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3–p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2–q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient.

Conclusions Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.