Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies

• Published in: Journal of human genetics Vol. 66; no. 11; pp. 1061 - 1068
• Main Authors: Miyamoto, Sachiko, Kato, Mitsuhiro, Hiraide, Takuya, Shiohama, Tadashi, Goto, Tomohide, Hojo, Akira, Ebata, Akio, Suzuki, Manabu, Kobayashi, Kozue, Chong, Pin Fee, Kira, Ryutaro, Matsushita, Hiroko Baber, Ikeda, Hiroko, Hoshino, Kyoko, Matsufuji, Mayumi, Moriyama, Nobuko, Furuyama, Masayuki, Yamamoto, Tatsuya, Nakashima, Mitsuko, Saitsu, Hirotomo
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2021
• Subjects: Adolescent; Adult; Agenesis of Corpus Callosum - complications; Agenesis of Corpus Callosum - diagnosis; Agenesis of Corpus Callosum - genetics; Agenesis of Corpus Callosum - pathology; Brain - diagnostic imaging; Brain - pathology; Brain Diseases - complications; Brain Diseases - diagnosis; Brain Diseases - genetics; Brain Diseases - pathology; Child; Child, Preschool; Congenital Abnormalities - diagnosis; Congenital Abnormalities - genetics; Congenital Abnormalities - pathology; Convulsions & seizures; Copy number; Corpus callosum; Corpus Callosum - diagnostic imaging; Corpus Callosum - pathology; DNA Copy Number Variations - genetics; Epilepsy; Female; Genetic analysis; Genetic factors; Genetics; Hospitals; Humans; Intellectual disabilities; Intellectual Disability - complications; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Intellectual Disability - pathology; Investigations; Japan; Lateral Ventricles - abnormalities; Lateral Ventricles - pathology; Magnetic resonance imaging; Male; Medicine; Motor Disorders - complications; Motor Disorders - diagnosis; Motor Disorders - genetics; Motor Disorders - pathology; Mutation - genetics; Nervous System Malformations - complications; Nervous System Malformations - diagnosis; Nervous System Malformations - genetics; Nervous System Malformations - pathology; Neuroimaging; Neurology; Patients; Pediatrics; Phenotype; Phenotypes; Seizures; Ventricle (lateral); Whole Exome Sequencing; Young Adult; Japan
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-021-00932-y

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.