title: Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy.
abstract: T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing (WES) was performed. The presumptive diagnoses were confirmed in 58 % of the enrolled patients (15/26) and involved 9 different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus-Merzbacher disease, with an incidence of 12 % (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH was 31 % (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes of hypomyelination were identified in six individuals (35 %, 6/17): TUBB4A, POLR3B, KCNT1, and MCOLN1, and some of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies.
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Arai-Ichinoi
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan. uematsu@bk9.so-net.ne.jp.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Uematsu
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sato
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kudo
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hino-Fukuyo
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8575, Japan.|Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryomachi, Aobaku, Sendai, 980-8573, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8575, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishiotoaza, Yumoto, Akiumachi, Taihakuku, Sendai, 982-0241, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002871:Chromosome Banding; D055028:Comparative Genomic Hybridization; D059472:Exome; D005260:Female; D018740:Genetic Heterogeneity; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male