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Published on: August 20, 2019
Phenotypic evolution of UNC80 loss of function
Elise Valkanas1, Katherine Schaffer1, Christopher Dunham2
1NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, National Institutes of Health, Bethesda, Maryland.
Insights
Two siblings with spastic paraplegia and developmental delay exhibited failure to thrive due to novel UNC80 gene mutations. This finding expands the known spectrum of UNC80-related disorders and highlights its role in neurodevelopment and growth.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Failure to thrive is a complex condition with diverse underlying causes.
- Hereditary spastic paraplegias (HSPs) are a group of inherited neurological disorders.
- Atypical presentations of HSPs can include global developmental delay and failure to thrive.
Purpose of the Study:
- To identify the genetic cause of spastic paraplegia, global developmental delay, and failure to thrive in two siblings.
- To expand the understanding of the phenotypic spectrum associated with UNC80 gene mutations.
Main Methods:
- Exome sequencing was performed to identify genetic variants.
- Clinical and biochemical investigations were conducted.
- Analysis of UNC80 mRNA levels in patient-derived fibroblasts was performed.
Main Results:
- Biallelic mutations in the UNC80 gene (NM_032504.1:c.[3983-3_3994delinsA];[2431C>T]) were identified.
- These mutations are predicted to result in loss of UNC80 function.
- Absence of detectable UNC80 mRNA suggests nonsense-mediated decay.
Conclusions:
- The identified UNC80 mutations are the likely cause of the observed phenotype in the siblings.
- This study expands the known disease spectrum of UNC80 mutations.
- UNC80 mutations should be considered in cases of unexplained spastic paraplegia with global developmental delay and failure to thrive.
Abstract:
Failure to thrive arises as a complication of a heterogeneous group of disorders. We describe two female siblings with spastic paraplegia and global developmental delay but also, atypically for the HSPs, poor weight gain classified as failure to thrive. After extensive clinical and biochemical investigations failed to identify the etiology, we used exome sequencing to identify biallelic UNC80 mutations (NM_032504.1:c.[3983-3_3994delinsA];[2431C>T]. The paternally inherited NM_032504.1:c.3983-3_3994delinsA is predicted to encode p.Ser1328Argfs*19 and the maternally inherited NM_032504.1:c.2431C>T is predicted to encode p.Arg811*. No UNC80 mRNA was detectable in patient cultured skin fibroblasts, suggesting UNC80 loss of function by nonsense mediated mRNA decay. Further supporting the UNC80 mutations as causative of these siblings' disorder, biallelic mutations in UNC80 have recently been described among individuals with an overlapping phenotype. This report expands the disease spectrum associated with UNC80 mutations. © 2016 Wiley Periodicals, Inc.
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