Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy

Sakamoto M 1 , Iwama K 1 , Sasaki M 2 , Ishiyama A 2 , Komaki H 2 , Saito T 2 Show all authors , Takeshita E 2 , Shimizu-Motohashi Y 2 , Haginoya K 3 , Kobayashi T 4 , Goto T 5 , Tsuyusaki Y 5 , Iai M 5 , Kurosawa K 6 , Osaka H 7 , Tohyama J 8 , Kobayashi Y 8 , Okamoto N 9 , Suzuki Y 10 , Kumada S 11 , Inoue K 11 , Mashimo H 11 , Arisaka A 11 , Kuki I 12 , Saijo H 13 , Yokochi K 14 , Kato M 15 , Inaba Y 16 , Gomi Y 17 , Saitoh S 18 , Shirai K 19 , Morimoto M 20 , Izumi Y 21 , Watanabe Y 22 , Nagamitsu SI 23 , Sakai Y 24 , Fukumura S 25 , Muramatsu K 26 , Ogata T 27 , Yamada K 28 , Ishigaki K 29 , Hirasawa K 29 , Shimoda K 30 , Akasaka M 31 , Kohashi K 32 , Sakakibara T 33 , Ikuno M 34 , Sugino N 35 , Yonekawa T 36 , Gürsoy S 37 , Cinleti T 38 , Kim CA 39 , Teik KW 40 , Yan CM 40 , Haniffa M 40 , Ohba C 41 , Ito S 42 , Saitsu H 43 , Saida K 41 , Tsuchida N 44 , Uchiyama Y 44 , Koshimizu E 41 , Fujita A 41 , Hamanaka K 41 , Misawa K 45 , Miyatake S 46 , Mizuguchi T 41 , Miyake N 47 , Matsumoto N 48

Affiliations 

  • 1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • 2 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
  • 3 Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai, Japan
  • 4 Department of Pediatrics, Tohoku University Hospital, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
  • 5 Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan
  • 6 Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
  • 7 Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan; Department of Pediatrics, Jichi Medical University, Tochigi, Japan
  • 8 Department of Child Neurology, NHO Nishiniigata Chuo Hospital, Niigata, Japan
  • 9 Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan
  • 10 Department of Pediatrics, Jichi Medical University, Tochigi, Japan
  • 11 Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
  • 12 Department of Pediatric Neurology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan
  • 13 Department of Pediatrics, Tokyo Metropolitan Higashiyamato Medical Center for Developmental/Multiple Disabilities, Tokyo, Japan
  • 14 Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Japan
  • 15 Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan
  • 16 Division of Neurology, Nagano Children's Hospital, Azumino, Nagano, Japan
  • 17 Division of Rehabilitation, Nagano Children's Hospital, Azumino, Nagano, Japan
  • 18 Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  • 19 Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
  • 20 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • 21 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  • 22 Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
  • 23 Department of Pediatrics, Fukuoka University Faculty of Medicine, Fukuoka, Japan
  • 24 Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • 25 Department of Pediatrics, School of Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
  • 26 Department of Pediatrics, Jichi Medical University, Tochigi, Japan; Department of Pediatrics, Graduate School of Medicine, Gunma University, Gunma, Japan
  • 27 Department of Pediatrics, Graduate School of Medicine, Gunma University, Gunma, Japan
  • 28 Department of Pediatric Neurology, Aichi Developmental Disability Center Central Hospital, Aichi, Japan
  • 29 Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan
  • 30 Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • 31 Department of Pediatrics, School of Medicine, Iwate Medical University, Iwate, Japan
  • 32 Department of Pediatrics, Matsudo City General Hospital, Matsudo, Japan
  • 33 Department of Pediatrics, Nara Medical University, Nara, Japan
  • 34 Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • 35 Department of Neonatology, Mie Chuo Medical Center, National Hospital Organization, Tsu, Japan
  • 36 Department of Pediatrics, Mie University School of Medicine, Mie, Japan
  • 37 Department of Pediatric Genetics, S.B.Ü. Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
  • 38 Department of Pediatric Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
  • 39 Unidade de Genética Clínica, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  • 40 Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
  • 41 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • 42 Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • 43 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
  • 44 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan
  • 45 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
  • 46 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan
  • 47 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
  • 48 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: naomat@yokohama-cu.ac.jp
Genet Med, 2022 Dec;24(12):2453-2463.
PMID: 36305856 DOI: 10.1016/j.gim.2022.08.007

Abstract

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.

METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.

RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.

CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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