Muhammad Ansar1, Saima Riazuddin2,3, Muhammad Tahir Sarwar4, Periklis Makrythanasis1,5, Sohail Aziz Paracha4, Zafar Iqbal6,7, Jamshed Khan4, Muhammad Zaman Assir3,8, Mureed Hussain2,6,9, Attia Razzaq6,9, Daniel Lôpo Polla6,10, Abid Sohail Taj4, Asbjørn Holmgren11, Naila Batool4, Doriana Misceo11, Justyna Iwaszkiewicz12, Arjan P M de Brouwer6, Michel Guipponi1,5, Sylviane Hanquinet13, Vincent Zoete12, Federico A Santoni1,5, Eirik Frengen11, Jawad Ahmed4, Sheikh Riazuddin3,8, Hans van Bokhoven6, Stylianos E Antonarakis14,15,16. 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. Stylianos.Antonarakis@unige.ch. 15. Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch. 16. iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch.
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.
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.
Authors: Muhammad Ansar; Hyung-Lok Chung; Ali Al-Otaibi; Mohammad Nael Elagabani; Thomas A Ravenscroft; Sohail A Paracha; Ralf Scholz; Tayseer Abdel Magid; Muhammad T Sarwar; Sayyed Fahim Shah; Azhar Ali Qaisar; Periklis Makrythanasis; Paul C Marcogliese; Erik-Jan Kamsteeg; Emilie Falconnet; Emmanuelle Ranza; Federico A Santoni; Hesham Aldhalaan; Ali Al-Asmari; Eissa Ali Faqeih; Jawad Ahmed; Hans-Christian Kornau; Hugo J Bellen; Stylianos E Antonarakis Journal: Am J Hum Genet Date: 2019-10-10 Impact factor: 11.025
Authors: Muhammad Ansar; Farid Ullah; Sohail A Paracha; Darius J Adams; Abbe Lai; Lynn Pais; Justyna Iwaszkiewicz; Francisca Millan; Muhammad T Sarwar; Zehra Agha; Sayyed Fahim Shah; Azhar Ali Qaisar; Emilie Falconnet; Vincent Zoete; Emmanuelle Ranza; Periklis Makrythanasis; Federico A Santoni; Jawad Ahmed; Nicholas Katsanis; Christopher Walsh; Erica E Davis; Stylianos E Antonarakis Journal: Am J Hum Genet Date: 2019-05-09 Impact factor: 11.025
Authors: Muhammad Ansar; Hyunglok Chung; Yar M Waryah; Periklis Makrythanasis; Emilie Falconnet; Ali Raza Rao; Michel Guipponi; Ashok K Narsani; Ralph Fingerhut; Federico A Santoni; Emmanuelle Ranza; Ali M Waryah; Hugo J Bellen; Stylianos E Antonarakis Journal: Hum Mol Genet Date: 2018-08-01 Impact factor: 6.150
Authors: Adam W Hansen; Mullai Murugan; He Li; Michael M Khayat; Liwen Wang; Jill Rosenfeld; B Kim Andrews; Shalini N Jhangiani; Zeynep H Coban Akdemir; Fritz J Sedlazeck; Allison E Ashley-Koch; Pengfei Liu; Donna M Muzny; Erica E Davis; Nicholas Katsanis; Aniko Sabo; Jennifer E Posey; Yaping Yang; Michael F Wangler; Christine M Eng; V Reid Sutton; James R Lupski; Eric Boerwinkle; Richard A Gibbs Journal: Am J Hum Genet Date: 2019-10-24 Impact factor: 11.025
Authors: Francesca Mattioli; Hossein Darvish; Sohail Aziz Paracha; Abbas Tafakhori; Saghar Ghasemi Firouzabadi; Marjan Chapi; Hafiz Muhammad Azhar Baig; Alexandre Reymond; Stylianos E Antonarakis; Muhammad Ansar Journal: NPJ Genom Med Date: 2021-11-11 Impact factor: 8.617