2. Academic Validation
  3. Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family

Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family

  • J Med Genet. 2016 Feb;53(2):138-44. doi: 10.1136/jmedgenet-2015-103179.
Rafiullah Rafiullah 1,  Muhammad Aslamkhan 2,  Nagarajan Paramasivam 3,  Christian Thiel 4,  Ghulam Mustafa 5,  Stefan Wiemann 6,  Matthias Schlesner 7,  Rebecca C Wade 5,  Gudrun A Rappold 8,  Simone Berkel 8
Affiliations

Affiliations

  • 1 Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
  • 2 Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
  • 3 Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
  • 4 Department I, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • 5 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.
  • 6 Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7 Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
  • 8 Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
PMID: 26566883 DOI: 10.1136/jmedgenet-2015-103179
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.

Methods and 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.

Conclusion: 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.

Keywords

Epilepsy and seizures; Genetics; Neurosciences; Psychotic disorders (incl schizophrenia).

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