TY - JOUR
T1 - Yunis-Varón syndrome caused by biallelic VAC14 mutations
AU - Lines, Matthew A.
AU - Ito, Yoko
AU - Kernohan, Kristin D.
AU - Mears, Wendy
AU - Hurteau-Miller, Julie
AU - Venkateswaran, Sunita
AU - Ward, Leanne
AU - Khatchadourian, Karine
AU - McClintock, Jeff
AU - Bhola, Priya
AU - Campeau, Philippe M.
AU - Boycott, Kym M.
AU - Michaud, Jean
AU - van Kuilenburg, André Bp
AU - Ferdinandusse, Sacha
AU - Dyment, David A.
PY - 2017
Y1 - 2017
N2 - 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
AB - 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
U2 - https://doi.org/10.1038/ejhg.2017.99
DO - https://doi.org/10.1038/ejhg.2017.99
M3 - Article
C2 - 28635952
SN - 1018-4813
VL - 25
SP - 1049
EP - 1054
JO - European journal of human genetics
JF - European journal of human genetics
IS - 9
ER -