title: Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.
abstract: BACKGROUND
  Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause.
  
  
  RESULTS
  Whole exome sequencing (WES) of a trio, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders.
  
  
  CONCLUSIONS
  This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder.
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
authors.forename: Rafiullah
authors.initials: R
authors.lastname: Rafiullah
authors.affiliation: Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslamkhan
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Paramasivam
authors.affiliation: Department I, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.affiliation: Molecular and Cellular Modeling (MCM) Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany Center for Molecular Biology, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Mustafa
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Molecular and Cellular Modeling (MCM) Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany Center for Molecular Biology, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wade
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Rappold
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Berkel
mesh_terms: D002675:Child, Preschool; D003241:Consanguinity; D004827:Epilepsy / Q000235:genetics; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D037102:Lectins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree
chemical_list: C477344:LMAN2L protein, human; D037102:Lectins; D026901:Membrane Transport Proteins
keywords: Epilepsy and seizures; Genetics; Neurosciences; Psychotic disorders (incl schizophrenia)