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Eur J Hum Genet. 2017 Sep;25(9):1049-1054. doi: 10.1038/ejhg.2017.99. Epub 2017 Jun 21.

Yunis-Varón syndrome caused by biallelic VAC14 mutations.

Author information

1
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
2
University of Ottawa, Ottawa, Ontario, Canada.
3
Department of Diagnostic Imaging, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
4
Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
5
Division of Pediatric Endocrinology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
6
Division of Pathology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
7
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
8
Department of Pediatrics, CHU Sainte Justine, Montréal, Québec, Canada.
9
Department of Pediatrics, University of Montréal, Montréal, Québec, Canada.
10
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
11
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.

Abstract

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.

PMID:
28635952
PMCID:
PMC5558182
DOI:
10.1038/ejhg.2017.99
[Indexed for MEDLINE]
Free PMC Article

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