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Abstract
Purpose
The "NALCN channelosome", is an ion channel complex consisting of multiple proteins
including NALCN, UNC79, UNC80, and FAM155A. NALCN and UNC80 variants are described
in a small number of individuals leading to a neurodevelopmental syndrome. However,
no pathogenic UNC79 variants have been reported and in vivo function of UNC79 in humans is largely unknown.
Methods
We used international gene-matching efforts to identify patients harboring ultra-rare
heterozygous loss-of-function UNC79 variants and no other putative responsible genes.
We used genetic manipulations in Drosophila and mice to test potential causal relationships
between UNC79 variants and the pathology.
Results
We found six unrelated and affected patients with UNC79 variants. Five patients presented
with overlapping neurodevelopmental features including mild to moderate intellectual
disability and a mild developmental delay while a single patient reportedly had normal
cognitive and motor development, but was diagnosed with epilepsy and autistic features.
All displayed behavioral issues and four patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function
variant have a developmental delay in body weight compared with wild-type. In addition,
they have impaired ability in learning and memory.
Conclusion
Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurological pathologies.
Key Words
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Article info
Publication history
Accepted:
May 7,
2023
Received in revised form:
May 5,
2023
Received:
November 23,
2022
Publication stage
In Press Accepted ManuscriptFootnotes
Disclosure:
The authors declare no conflict of interest.
We received and archived written consent for participation/publication from every individual whose data is included.
We have received and archived a valid HIPAA authorization for participation/publication from every individual whose PHI is included and whose photo is included. Concent for photos was received.
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
