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Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family
  1. Rafiullah Rafiullah1,2,
  2. Muhammad Aslamkhan2,
  3. Nagarajan Paramasivam3,4,
  4. Christian Thiel5,
  5. Ghulam Mustafa6,7,
  6. Stefan Wiemann8,
  7. Matthias Schlesner4,
  8. Rebecca C Wade6,7,
  9. Gudrun A Rappold1,
  10. Simone Berkel1
  1. 1Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
  2. 2Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan
  3. 3Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany
  4. 4Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
  5. 5Department I, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
  6. 6Molecular and Cellular Modeling (MCM) Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
  7. 7Center for Molecular Biology, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany
  8. 8Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
  1. Correspondence to Professor Gudrun A Rappold, Department of Human Molecular Genetics, Institute of Human Genetics, Im Neuenheimer Feld 366, Heidelberg 69120, Germany; gudrun.rappold{at}med.uni-heidelberg.de

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.

  • Epilepsy and seizures
  • Genetics
  • Neurosciences
  • Psychotic disorders (incl schizophrenia)

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