Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family
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 consanguineou...
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| Hauptverfasser: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2016
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| In: |
Journal of medical genetics
Year: 2016, Jahrgang: 53, Heft: 2, Pages: 138-144 |
| ISSN: | 1468-6244 |
| DOI: | 10.1136/jmedgenet-2015-103179 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/jmedgenet-2015-103179 Verlag, lizenzpflichtig, Volltext: https://jmg.bmj.com/content/53/2/138 
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| Verfasserangaben: | Rafiullah Rafiullah, Muhammad Aslamkhan, Nagarajan Paramasivam, Christian Thiel, Ghulam Mustafa, Stefan Wiemann, Matthias Schlesner, Rebecca C Wade, Gudrun A Rappold, Simone Berkel |
| Zusammenfassung: | 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. |
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| Beschreibung: | Published Online First 13 November 2015 Gesehen am 17.07.2020 |
| Beschreibung: | Online Resource |
| ISSN: | 1468-6244 |
| DOI: | 10.1136/jmedgenet-2015-103179 |