Pathogenic variants of <i>DYNC2H1</i>, <i>KIAA0556</i>, and <i>PTPN11</i> associated with hypothalamic hamartoma.

Abstract

Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH). 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. We identified a germline variant of <i>KIAA0556</i>, which encodes a ciliary protein, and 2 somatic variants of <i>PTPN11</i>, 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 <i>DYNC2H1</i>, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of <i>DYNC2H1</i> arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of <i>DYNC2H1</i>). Furthermore, a combination of a germline and a somatic <i>DYNC2H1</i> variant was detected in another patient. 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.