Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma. (16th July 2019)

• Record Type: Journal Article
• Authors: Fujita, Atsushi; Higashijima, Takefumi; Shirozu, Hiroshi; Masuda, Hiroshi; Sonoda, Masaki; Tohyama, Jun; Kato, Mitsuhiro; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Mitsuhashi, Satomi; Mizuguchi, Takeshi; Takata, Atsushi; Miyatake, Satoko; Miyake, Noriko; Fukuda, Masafumi; Kameyama, Shigeki; Saitsu, Hirotomo; Matsumoto, Naomichi
• Is Part Of: Neurology. Volume 93:Number 3(2019)
• Publication Date: 2019-07-16
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000007774
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : 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.