Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease.
In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14.
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Guy M
GM
Lenk
Department of Child Psychiatry, Warsaw Medical University, 02-106 Warsaw, Poland; Department of Experimental and Clinical Neuropathology, Medical Research Center, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Krystyna
K
Szymanska
Klinik für Neurologie, Universitätsklinikum Magdeburg, 39120 Magdeburg, Germany.
Grazyna
G
Debska-Vielhaber
Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
Malgorzata
M
Rydzanicz
Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
Anna
A
Walczak
Department of Diagnostic Imaging, Institute of Mother and Child, 01-211 Warsaw, Poland.
Monika
M
Bekiesinska-Figatowska
Klinik für Neurologie, Universitätsklinikum Magdeburg, 39120 Magdeburg, Germany.
Stefan
S
Vielhaber
Klinik für Epileptologie and Life&Brain Center, Universitätsklinikum Bonn, 53105 Bonn, Germany.
Kerstin
K
Hallmann
Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland; Institute of Physiology and Pathology of Hearing, 05-830 Nadarzyn, Poland.
Piotr
P
Stawinski
Madison, WI 53711, USA.
Sonja
S
Buehring
Department of Neurology, University of Wisconsin-Madison, Madison, WI 53705, USA.
David A
DA
Hsu
Klinik für Epileptologie and Life&Brain Center, Universitätsklinikum Bonn, 53105 Bonn, Germany.
Wolfram S
WS
Kunz
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA. Electronic address: meislerm@umich.edu.
Miriam H
MH
Meisler
Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland. Electronic address: rploski@wp.pl.
Rafal
R
Ploski
D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics*; D010375:Pedigree
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C494631:VAC14 protein, human