Atsushi Fujita1, Takefumi Higashijima1, Hiroshi Shirozu1, Hiroshi Masuda1, Masaki Sonoda1, Jun Tohyama1, Mitsuhiro Kato1, Mitsuko Nakashima1, Yoshinori Tsurusaki1, Satomi Mitsuhashi1, Takeshi Mizuguchi1, Atsushi Takata1, Satoko Miyatake1, Noriko Miyake1, Masafumi Fukuda1, Shigeki Kameyama1, Hirotomo Saitsu1, Naomichi Matsumoto2. 1. From the Departments of Human Genetics (A.F., S. Mitsuhashi, T.M., A.T., S. Miyatake, N. Miyake, N. Matsumoto) and Neurosurgery (M.S.), Yokohama City University Graduate School of Medicine; Departments of Functional Neurosurgery (T.H., H. Shirozu, H.M., M.F., S.K.) and Child Neurology (J.T.), Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital Niigata, Japan; Department of Pediatrics and Neurology (M.S.), Wayne State University, Children's Hospital of Michigan, Detroit Medical Center; Department of Pediatrics (M.K.), Showa University School of Medicine, Tokyo; Department of Biochemistry (M.N., H. Saitsu), Hamamatsu University School of Medicine; and Clinical Research Institute (Y.T.), Kanagawa Children's Medical Center, Yokohama, Japan. 2. From the Departments of Human Genetics (A.F., S. Mitsuhashi, T.M., A.T., S. Miyatake, N. Miyake, N. Matsumoto) and Neurosurgery (M.S.), Yokohama City University Graduate School of Medicine; Departments of Functional Neurosurgery (T.H., H. Shirozu, H.M., M.F., S.K.) and Child Neurology (J.T.), Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital Niigata, Japan; Department of Pediatrics and Neurology (M.S.), Wayne State University, Children's Hospital of Michigan, Detroit Medical Center; Department of Pediatrics (M.K.), Showa University School of Medicine, Tokyo; Department of Biochemistry (M.N., H. Saitsu), Hamamatsu University School of Medicine; and Clinical Research Institute (Y.T.), Kanagawa Children's Medical Center, Yokohama, Japan. naomat@yokohama-cu.ac.jp.
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.
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.
Authors: Juliana Minardi Nascimento; Danielle Gouvêa-Junqueira; Giuliana S Zuccoli; Carolina da Silva Gouveia Pedrosa; Caroline Brandão-Teles; Fernanda Crunfli; André S L M Antunes; Juliana S Cassoli; Karina Karmirian; José Alexandre Salerno; Gabriela Fabiano de Souza; Stéfanie Primon Muraro; Jose Luiz Proenca-Módena; Luiza M Higa; Amilcar Tanuri; Patricia P Garcez; Stevens K Rehen; Daniel Martins-de-Souza Journal: Mol Neurobiol Date: 2022-06-22 Impact factor: 5.682
Authors: Timothy E Green; Joshua E Motelow; Mark F Bennett; Zimeng Ye; Caitlin A Bennett; Nicole G Griffin; John A Damiano; Richard J Leventer; Jeremy L Freeman; A Simon Harvey; Paul J Lockhart; Lynette G Sadleir; Amber Boys; Ingrid E Scheffer; Heather Major; Benjamin W Darbro; Melanie Bahlo; David B Goldstein; John F Kerrigan; Erin L Heinzen; Samuel F Berkovic; Michael S Hildebrand Journal: Hum Mol Genet Date: 2022-07-21 Impact factor: 5.121
Authors: Marcello Niceta; Maria Lisa Dentici; Andrea Ciolfi; Romana Marini; Sabina Barresi; Francesca Romana Lepri; Antonio Novelli; Enrico Bertini; Marco Cappa; Maria Cristina Digilio; Bruno Dallapiccola; Marco Tartaglia Journal: BMC Pediatr Date: 2020-03-12 Impact factor: 2.125
Authors: Nathan T Cohen; J Helen Cross; Alexis Arzimanoglou; Samuel F Berkovic; John F Kerrigan; Ilene Penn Miller; Erica Webster; Lisa Soeby; Arthur Cukiert; Dale K Hesdorffer; Barbara L Kroner; Clifford B Saper; Andreas Schulze-Bonhage; William D Gaillard Journal: Neurology Date: 2021-10-04 Impact factor: 9.910