Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Genet Med. 2018 Jul;20(7):778-784. doi: 10.1038/gim.2017.113.

Muhammad Ansar ¹, Saima Riazuddin ² ³, Muhammad Tahir Sarwar ⁴, Periklis Makrythanasis ¹ ⁵, Sohail Aziz Paracha ⁴, Zafar Iqbal ⁶ ⁷, Jamshed Khan ⁴, Muhammad Zaman Assir ³ ⁸, Mureed Hussain ² ⁶ ⁹, Attia Razzaq ⁶ ⁹, Daniel Lôpo Polla ⁶ ¹⁰, Abid Sohail Taj ⁴, Asbjørn Holmgren ¹¹, Naila Batool ⁴, Doriana Misceo ¹¹, Justyna Iwaszkiewicz ¹², Arjan P M de Brouwer ⁶, Michel Guipponi ¹ ⁵, Sylviane Hanquinet ¹³, Vincent Zoete ¹², Federico A Santoni ¹ ⁵, Eirik Frengen ¹¹, Jawad Ahmed ⁴, Sheikh Riazuddin ³ ⁸, Hans van Bokhoven ⁶, Stylianos E Antonarakis ¹⁴ ¹⁵ ¹⁶

Affiliations

1 Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
2 Department of Otorhinolaryngology-Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
3 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
4 Department of Molecular Biology and Genetics, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan.
5 Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
6 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviou, Radboud University Medical Center, Nijmegen, The Netherlands.
7 Department of Neurology, Oslo University Hospital, Oslo, Norway.
8 Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
9 National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
10 Center for Genetic Diseases, CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
11 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
12 Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland.
13 Department of Pediatric Radiology, Geneva University Children's Hospital, Geneva, Switzerland.
14 Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. [email protected].
15 Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. [email protected].
16 iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland. [email protected].

PMID: 28837161 DOI: 10.1038/gim.2017.113

Abstract

Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.

Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.

Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.

Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

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