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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
ACMG Member Login
Are you an ACMG Member? Sign in for online access.Subscribe:
Subscribe to Genetics in MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Differential diagnosis of cerebellar atrophy in childhood: an update.Neuropediatrics. 2015; 46: 359-370https://doi.org/10.1055/s-0035-1564620
- Differential diagnosis of cerebellar atrophy in childhood.Eur J Paediatr Neurol. 2008; 12: 155-167https://doi.org/10.1016/j.ejpn.2007.07.010
- Diagnostic approach to cerebellar hypoplasia.Cerebellum. 2021; 20: 631-658https://doi.org/10.1007/s12311-020-01224-5
- Insights into cerebellar development and connectivity.Neurosci Lett. 2019; 688: 2-13https://doi.org/10.1016/j.neulet.2018.05.013
- Cerebellar ataxia in children: A clinical and MRI approach to the differential diagnosis. Top Magn Reson Imaging. 2018;27(4):275-302. Published correction appears in.Top Magn Reson Imaging. 2018; 27: 385https://doi.org/10.1097/RMR.0000000000000175
- Triple representation of language, working memory, social and emotion processing in the cerebellum: convergent evidence from task and seed-based resting-state fMRI analyses in a single large cohort.Neuroimage. 2018; 172: 437-449https://doi.org/10.1016/j.neuroimage.2018.01.082
- Redefining the etiologic landscape of cerebellar malformations.Am J Hum Genet. 2019; 105: 606-615https://doi.org/10.1016/j.ajhg.2019.07.019
- Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood.Neurogenetics. 2013; 14: 225-232https://doi.org/10.1007/s10048-013-0375-8
- Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms.J Hum Genet. 2022; 67: 157-164https://doi.org/10.1038/s10038-021-00986-y
- ToppGene Suite for gene list enrichment analysis and candidate gene prioritization.Nucleic Acids Res. 2009; 37: W305-W311https://doi.org/10.1093/nar/gkp427
- STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.Nucleic Acids Res. 2019; 47: D607-D613https://doi.org/10.1093/nar/gky1131
- De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.J Hum Genet. 2015; 60: 739-742https://doi.org/10.1038/jhg.2015.108
- De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality.Hum Mol Genet. 2021; 31: 69-81https://doi.org/10.1093/hmg/ddab224
- De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.Brain. 2018; 141: 1703-1718https://doi.org/10.1093/brain/awy092
- De novo mutations in protein kinase genes CAMK2A and CAMK2B cause intellectual disability.Am J Hum Genet. 2017; 101: 768-788https://doi.org/10.1016/j.ajhg.2017.10.003
- A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects.Neurogenetics. 2016; 17: 173-178https://doi.org/10.1007/s10048-016-0482-4
- Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy.Clin Genet. 2021; 100: 722-730https://doi.org/10.1111/cge.14066
- Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.Nat Commun. 2021; 12: 2558https://doi.org/10.1038/s41467-021-22627-w
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
- Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245-257. Published correction appears in.Genet Med. 2021; 23: 2230https://doi.org/10.1038/s41436-019-0686-8
- Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.Neurotherapeutics. 2019; 16: 263-286https://doi.org/10.1007/s13311-018-00696-y
- Spinocerebellar ataxia: an update.J Neurol. 2019; 266: 533-544https://doi.org/10.1007/s00415-018-9076-4
- A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.Brain. 2017; 140: 1579-1594https://doi.org/10.1093/brain/awx081
- Updated frequency analysis of spinocerebellar ataxia in China.Brain. 2018; 141: e22https://doi.org/10.1093/brain/awy016
- The classification of autosomal recessive cerebellar ataxias: a consensus statement from the society for research on the cerebellum and ataxias task force.Cerebellum. 2019; 18: 1098-1125https://doi.org/10.1007/s12311-019-01052-2
- Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app.Orphanet J Rare Dis. 2021; 16: 170https://doi.org/10.1186/s13023-021-01727-2
- Arginase-1 deficiency.J Mol Med (Berl). 2015; 93: 1287-1296https://doi.org/10.1007/s00109-015-1354-3
- Cerebral folate deficiency: analytical tests and differential diagnosis.J Inherit Metab Dis. 2019; 42: 655-672https://doi.org/10.1002/jimd.12092
- Study of intraventricular cerliponase Alfa for CLN2 disease.N Engl J Med. 2018; 378: 1898-1907https://doi.org/10.1056/NEJMoa1712649
- Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2.Hum Mol Genet. 2017; 26: 3935-3945https://doi.org/10.1093/hmg/ddx281
- 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6.Sci Rep. 2016; 629489https://doi.org/10.1038/srep29489
- Ion channel dysfunction in cerebellar ataxia.Neurosci Lett. 2019; 688: 41-48https://doi.org/10.1016/j.neulet.2018.02.005
- Disrupted calcium signaling in animal models of human spinocerebellar ataxia (SCA).Int J Mol Sci. 2019; 21: 216https://doi.org/10.3390/ijms21010216
- Cerebellar degeneration in epilepsy: A systematic review.Int J Environ Res Public Health. 2021; 18: 473https://doi.org/10.3390/ijerph18020473
Article info
Publication history
Published online: October 28, 2022
Accepted:
August 15,
2022
Received in revised form:
August 15,
2022
Received:
May 10,
2022
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
