Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia.
Genet Med
; 26(7): 101143, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38641995
ABSTRACT
PURPOSE:
Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive.METHODS:
We studied 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing.RESULTS:
We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from 2 unrelated families segregated 2 homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of 2 affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process.CONCLUSION:
Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Pedigree
/
Neurodevelopmental Disorders
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Loss of Function Mutation
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Microcephaly
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Muscle Hypotonia
Limits:
Child
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Child, preschool
/
Female
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Humans
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Infant
/
Male
Language:
En
Journal:
Genet Med
Journal subject:
GENETICA MEDICA
Year:
2024
Type:
Article
Affiliation country:
Germany