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

Article Article scientifique Article Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay eng 2018 author Ansar Muhammad 810392 author Riazuddin Saima author Sarwar Muhammad Tahir 882869 author Makrythanasis Periklis 638085 author Paracha Sohail Aziz author Iqbal Zafar author Khan Jamshed author Assir Muhammad Zaman author Hussain Mureed author Razzaq Attia author Polla Daniel Lôpo author Taj Abid Sohail author Holmgren Asbjørn author Batool Naila 862693 author Misceo Doriana author Iwaszkiewicz Justyna 677092 author de Brouwer Arjan P M author Guipponi Michel 118157 author Hanquinet Sylviane 133458 author Zoete Vincent author Santoni Federico A author Frengen Eirik author Ahmed Jawad author Riazuddin Sheikh author van Bokhoven Hans author Antonarakis Stylianos 22813 778-784 10.1038/gim.2017.113 28837161 1098-3600 PurposeTo elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.MethodsA 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.ResultsAll 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.ConclusionLINGO1 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.GENETICS in MEDICINE advance online publication, 24 August 2017; doi:10.1038/gim.2017.113. Consanguineous families Developmental delay Intellectual disability LINGO1 Dewey 576.5 Dewey 616.0757 Dewey 590 Dewey 618 European Commission Genetic and Epigenetic Networks in Cognitive Dysfunction 241995 GENCODYS EU FP7 23 Institut de génétique et de génomique 0DH 135 Département de médecine génétique et développement 21D 58 Département de pédiatrie, gynécologie et obstétrique 223 62 Département de radiologie et informatique médicale 227 false 1284 NCCR Synapsy 504 Radiologie neuro-diagnostique et neuro-interventionnelle en pédiatrie 842 Genetics in Medicine 20 7 1e839d0b-b047-46d4-a935-ade787e15672 Article (Published version) Public gim2017113.pdf 3338116 application/pdf CC BY openAccess Centres et instituts / Institut de génétique et de génomique Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique Faculté de médecine / Section de médecine clinique / Département de radiologie et informatique médicale

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Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay	Genetics in Medicine			2018	585	345

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Sarwar, Muhammad Tahir