Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts.
BACKGROUND
Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively.


METHODS
Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families.


RESULTS
Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%).


CONCLUSIONS
Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.|Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Kazuhiro
http://orcid.org/0000-0002-2584-9524
K
Iwama
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Takeshi
T
Mizuguchi
Department of Pediatrics and Pediatric Neurology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan.
Jun-Ichi
JI
Takanashi
Department of Neurology, Kameda Medical Center, Kamogawa, Japan.
Hidehiro
H
Shibayama
Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
Minobu
M
Shichiji
Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
Susumu
S
Ito
Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
Hirokazu
H
Oguni
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
Toshiyuki
T
Yamamoto
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Akiko
A
Sekine
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Shun
S
Nagamine
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Yoshio
Y
Ikeda
Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
Hiroya
H
Nishida
Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
Satoko
S
Kumada
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takeshi
T
Yoshida
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tomonari
T
Awaya
Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Ryuta
R
Tanaka
Department of Neurology, Kariya Toyota General Hospital, Kariya, Japan.
Ryo
R
Chikuchi
Department of Neurology, Kariya Toyota General Hospital, Kariya, Japan.
Hisayoshi
H
Niwa
Department of Neurosurgery, Nagoya City University Hospital, Nagoya, Japan.
Yu-Ichi
YI
Oka
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Satoko
S
Miyatake
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Mitsuko
M
Nakashima
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Atsushi
A
Takata
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Noriko
N
Miyake
Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Shuichi
S
Ito
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Hirotomo
H
Saitsu
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Naomichi
N
Matsumoto
D000328:Adult; D000483:Alleles; D001921:Brain / Q000503:physiopathology; D002114:Calcinosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D020863:Central Nervous System Cysts / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D003560:Cysts / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D056784:Leukoencephalopathies / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D020537:RNA, Small Nucleolar / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics
D020537:RNA, Small Nucleolar; D034501:Telomere-Binding Proteins; C544945:Ctc1 protein, human; C000626792:SNORD118 RNA, human
CRMCC; Coats plus syndrome; LCC; SNORD118; snoRNA