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Cold Spring Harb Mol Case Stud. 2019 Dec 13;5(6). pii: a003715. doi: 10.1101/mcs.a003715. Print 2019 Dec.

VAC14 syndrome in two siblings with retinitis pigmentosa and neurodegeneration with brain iron accumulation.

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NYS Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, New York 10314, USA.
Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, New York 11211, USA.
Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel.
Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel.
Department of Radiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Columbia University Irving Medical Center, The Neurological Institute, New York, New York 10032, USA.
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Congenica Ltd, Biodata Innovation Centre, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York 10032, USA.


Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (nonsyndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies.


moderate global developmental delay; retinitis pigmentosa inversa

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