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Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease

BACKGROUND: Krabbe disease, also called globoid cell leukodystrophy, is an autosomal recessive disease caused by a deficiency of lysosomal galactocerebrosidase. Infantile Krabbe occurring before 12 months of age accounts for most cases. Typical clinical features include irritability, seizures, perip...

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Autores principales: Zhang, Xiaoli, Niu, Guohui, Song, Panpan, Wang, Lijun, Han, Rui, Chu, Manman, Guo, Qiliang, Xu, Zhao, Yan, Lihong, Jia, Tianming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578788/
https://www.ncbi.nlm.nih.gov/pubmed/34765479
http://dx.doi.org/10.21037/tp-21-403
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author Zhang, Xiaoli
Niu, Guohui
Song, Panpan
Wang, Lijun
Han, Rui
Chu, Manman
Guo, Qiliang
Xu, Zhao
Yan, Lihong
Jia, Tianming
author_facet Zhang, Xiaoli
Niu, Guohui
Song, Panpan
Wang, Lijun
Han, Rui
Chu, Manman
Guo, Qiliang
Xu, Zhao
Yan, Lihong
Jia, Tianming
author_sort Zhang, Xiaoli
collection PubMed
description BACKGROUND: Krabbe disease, also called globoid cell leukodystrophy, is an autosomal recessive disease caused by a deficiency of lysosomal galactocerebrosidase. Infantile Krabbe occurring before 12 months of age accounts for most cases. Typical clinical features include irritability, seizures, peripheral neuropathy, and progressive neurodegeneration. METHODS: We collected and summarized the clinical and genetic data of an 8-month-old boy who demonstrated Krabbe disease onset at around 6 months. Potential pathogenic variants were screened by whole exome sequencing, and effects of candidate variants on alternative transcript and truncated protein were further validated at the RNA and protein level. RESULTS: Galactocerebrosidase activity was nearly absent in his blood, and whole exome sequencing revealed compound heterozygous variants [NM_000153.4: (c.658C>T); (c.328+5G>T)] in galactosylceramidase (GALC). The variant c.328+5G>T was predicted to alter splicing, and the abnormal isoform transcript was validated by observation of abnormal RNA isoforms. The variant c.658C>T was predicted to cause truncation of the protein, which was validated by western blotting. CONCLUSIONS: Our findings revealed compound heterozygous variants with solid experimental results for Krabbe disease and provides strong evidence for further Krabbe disease screening and clinical consulting. As a rare inherited systemic disorder, genetic variants in Krabbe disease should be investigated, as experimental validation for clinical diagnosis is needed.
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spelling pubmed-85787882021-11-10 Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease Zhang, Xiaoli Niu, Guohui Song, Panpan Wang, Lijun Han, Rui Chu, Manman Guo, Qiliang Xu, Zhao Yan, Lihong Jia, Tianming Transl Pediatr Original Article BACKGROUND: Krabbe disease, also called globoid cell leukodystrophy, is an autosomal recessive disease caused by a deficiency of lysosomal galactocerebrosidase. Infantile Krabbe occurring before 12 months of age accounts for most cases. Typical clinical features include irritability, seizures, peripheral neuropathy, and progressive neurodegeneration. METHODS: We collected and summarized the clinical and genetic data of an 8-month-old boy who demonstrated Krabbe disease onset at around 6 months. Potential pathogenic variants were screened by whole exome sequencing, and effects of candidate variants on alternative transcript and truncated protein were further validated at the RNA and protein level. RESULTS: Galactocerebrosidase activity was nearly absent in his blood, and whole exome sequencing revealed compound heterozygous variants [NM_000153.4: (c.658C>T); (c.328+5G>T)] in galactosylceramidase (GALC). The variant c.328+5G>T was predicted to alter splicing, and the abnormal isoform transcript was validated by observation of abnormal RNA isoforms. The variant c.658C>T was predicted to cause truncation of the protein, which was validated by western blotting. CONCLUSIONS: Our findings revealed compound heterozygous variants with solid experimental results for Krabbe disease and provides strong evidence for further Krabbe disease screening and clinical consulting. As a rare inherited systemic disorder, genetic variants in Krabbe disease should be investigated, as experimental validation for clinical diagnosis is needed. AME Publishing Company 2021-10 /pmc/articles/PMC8578788/ /pubmed/34765479 http://dx.doi.org/10.21037/tp-21-403 Text en 2021 Translational Pediatrics. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Original Article
Zhang, Xiaoli
Niu, Guohui
Song, Panpan
Wang, Lijun
Han, Rui
Chu, Manman
Guo, Qiliang
Xu, Zhao
Yan, Lihong
Jia, Tianming
Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease
title Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease
title_full Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease
title_fullStr Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease
title_full_unstemmed Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease
title_short Compound heterozygous pathogenic variants in the GALC gene cause infant-onset Krabbe disease
title_sort compound heterozygous pathogenic variants in the galc gene cause infant-onset krabbe disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578788/
https://www.ncbi.nlm.nih.gov/pubmed/34765479
http://dx.doi.org/10.21037/tp-21-403
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