A novel homozygous GALC variant has been associated with Krabbe disease in a consanguineous family
Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal storage disorder involving the white matter of the peripheral and the central nervous systems. It is caused by a deficiency of galactocerebrosidase enzyme activity. The most common manifestation is the classical early onset KD that leads to patient’s loss before the age of 2. Herein, we report the evaluation of a consanguineous family with three affected children manifesting severe neurological findings that ended with death before the age of 2, in an attempt to provide genetic diagnosis to the family. One of the children underwent detailed physical and neurological examinations, including brain magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) evaluations. GALC genetic testing on this child enabled identification of a novel homozygous variant (NM_000153.3: c.1394C>T; p.(Thr465Ile)), which confirmed diagnosis as KD. Familial segregation of this variant was performed by PCR amplification and Sanger sequencing that revealed the parents as heterozygous carriers. We believe this novel GALC variant will not only help in genetic counseling to this family but will also aid in identification of future KD cases.
KeywordsKrabbe disease GALC Genetic analysis Novel variation Consanguinity
The authors are grateful to the patients and their relatives for their participation in this study.
We would like to acknowledge Advanced Genomics and Bioinformatics Research Center (IGBAM), TUBITAK MAM-GMBE, for kindly providing variant frequency data of 1182 exome sequenced individuals from Turkey with varying disorders, which was used as a population control set towards the evaluation of the novel GALC variant. We would also like to acknowledge Sedef Iskit, PhD, for technical assistance towards the construction of the artwork.
Feyza Nur Tuncer (FNT) and Sibel Aylin Ugur Iseri (SAUI) were involved in genetic evaluation of the recruited family members, data acquisition, and analyses. FNT has written the original draft, which subsequently was edited by SAUI. Mahmut Demir (MD), Meryem Karaca (MK), and Mustafa Calik (MC) were involved in clinical evaluations of the patients, interview with the available family members and in commenting of several drafts of the manuscript. Zuhal Yapici (ZY) took role both in the evaluation of the patients’ MRI and writing the clinical findings in the main draft. MC mentored the study.
This work was supported by the grant of The Scientific and Technology Research Council of Turkey (TUBITAK) Project Number: 113S331. Biobanking support was provided by Istanbul Development Agency (ISTKA) Project Number: TR10/15/YNK/0093.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Accordingly, informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare that they have no conflicts of interest.
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