Loss-of-function mutation in RUSC2 causes intellectual disability and secondary microcephaly.
Inherited aberrancies in intracellular vesicular transport are associated with a variety of neurological and non-neurological diseases. RUSC2 is a gene found on chromosome 9p13.3 that codes for iporin, a ubiquitous protein with high expression in the brain that interacts with Rab proteins (GTPases implicated in intracellular protein trafficking). Although mutations in Rab proteins have been described as causing brain abnormalities and intellectual disability, until now no disease-causing mutations in RUSC2 have ever been reported in humans. We describe, to our knowledge for the first time, three patients with inherited homozygous nonsense mutations identified in RUSC2 on whole-exome sequencing. All three patients had central hypotonia, microcephaly, and moderate to severe intellectual disability. Two patients had additional features of early-onset epilepsy and absence of the splenium. This report adds to the ever-expanding landscape of genetic causes of intellectual disability and increases our understanding of the cellular processes underlying this important neurological entity.
Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
Ali H
AH
Alwadei
Division of Pediatric Neurology, Montreal Children's Hospital, Montreal, QC, Canada.
Ruba
R
Benini
Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
Adel
A
Mahmoud
Medical Genetics Division, Specialized Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
Ali
A
Alasmari
Genome Diagnostics Nijmegen, Department of Medical Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Erik-Jan
EJ
Kamsteeg
Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
Majid
M
Alfadhel
D000293:Adolescent; D061085:Agenesis of Corpus Callosum / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004827:Epilepsy / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D010375:Pedigree
D002352:Carrier Proteins; C509346:RUSC2 protein, human