title: A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency.
abstract: BACKGROUND
  Numerous syndromic forms of intellectual disability have been described including those with abnormal sweating pattern.
  
  
  OBJECTIVE
  To describe the clinical and molecular analysis of a large multiplex consanguineous Saudi family with an unusual constellation of severe intellectual disability, hypohidrosis, abnormal teeth, and acquired microcephaly.
  
  
  METHODS
  Clinical evaluation, autozygosity mapping, exome sequencing, and expression analysis.
  
  
  RESULTS
  Autozygosity mapping revealed a single critical locus corresponding to chr13:39 338 062-40 857 430. Exome sequencing uncovered a deep intronic (NM_020751.2:c.1167-24A>G) variant in COG6 that largely replaces the consensus acceptor site, resulting in pronounced reduction of the normal transcript and consequent deficiency of COG6 protein. Patient cells also exhibited pronounced deficiency of STX6, consistent with the established stabilising effect of COG6 on STX6. Four additional patients representing two families of the same tribal origin as the original family were found to have the same mutation, confirming a founder effect. Remarkably, none of the patients displayed any detectable abnormality in the glycosylation pattern of transferrin, which contradicts a previously published report of a patient whose abnormal glycosylation pattern was presumed to be caused by a missense variant in COG6.
  
  
  CONCLUSIONS
  Our data implicate COG6 in the pathogenesis of a novel hypohidrotic disorder in humans that is distinct from congenital disorders of glycosylation.
authors.affiliation: Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, MBC-03 PO BOX 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.forename: Shinu
authors.initials: S
authors.lastname: Ansari
authors.forename: Muneera J
authors.initials: MJ
authors.lastname: Alshammari
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkhalidi
authors.forename: Hadeel
authors.initials: H
authors.lastname: Alrukban
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D006031:Glycosylation; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D013577:Syndrome
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C553748:COG6 protein, human
keywords: cdg; exome; golgi; hypohidrosis; intellectual disability