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MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)
  1. Abolfazl Rad1,2,
  2. Umut Altunoglu3,
  3. Rebecca Miller4,
  4. Reza Maroofian5,
  5. Kiely N James6,
  6. Ahmet Okay Çağlayan7,8,
  7. Maryam Najafi1,
  8. Valentina Stanley6,
  9. Rose-Mary Boustany9,10,
  10. Gözde Yeşil11,
  11. Afsaneh Sahebzamani12,
  12. Gülhan Ercan-Sencicek7,
  13. Kolsoum Saeidi13,14,
  14. Kaman Wu1,
  15. Peter Bauer15,
  16. Zeineb Bakey1,16,
  17. Joseph G Gleeson6,
  18. Natalie Hauser4,
  19. Murat Gunel7,
  20. Hulya Kayserili3,17,
  21. Miriam Schmidts1,16
  1. 1 Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
  3. 3 Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, Istanbul, Turkey
  4. 4 Inova Cardiovascular Genomics Clinic, Inova Translational Medicine Institute, Falls Church, Virginia, USA
  5. 5 Genetics and Molecular Cell Sciences Research Centre, St George’s, University of London, London, UK
  6. 6 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children’s Institute for Genomic Medicine, University of California, San Diego, California, USA
  7. 7 Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, Connecticut, USA
  8. 8 Medical Genetics Department, Bilim University School of Medicine, İstanbul, Turkey
  9. 9 Department of Pediatrics and Adolescent Medicine, Neurogenetics Program and Division of Pediatric Neurology, American University of Beirut Medical Center Special Kids Clinic, Beirut, Lebanon
  10. 10 Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
  11. 11 Medical Genetics Department, Bezmi Alem University School of Medicine, Istanbul, Turkey
  12. 12 Paediatric and Genetic Counselling Center, Kerman Welfare Organization, Kerman, Iran
  13. 13 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
  14. 14 Department of Medical Genetics, Kerman University of Medical Sciences, Kerman, Iran
  15. 15 Centogene AG, Rostock, Germany
  16. 16 Pediatrics Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany
  17. 17 Medical Genetics Department, Koç University School of Medicine (KUSoM), İstanbul, Turkey
  1. Correspondence to Dr Miriam Schmidts, Human Genetics Department, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands and Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Medical Faculty, 79112 Freiburg, Germany; Miriam.Schmidts{at}


Background Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.

Objective A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families.

Results We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly.

Conclusion This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.

  • MAB21L1
  • corneal dystrophy
  • scrotal/labial aplasia
  • pontocerebellar hypoplasia
  • Cerebello-Oculo-Facio-genital (COFG) syndrome

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  • NH, MG, HK and MS contributed equally.

  • AR, UA, RM and RM contributed equally.

  • Contributors All authors fulfil the criteria for authorship. AR, RM, RM, UA, KNJ, VS, AOC, MN, KW, ZB, RMB, PB and PM analysed and interpreted NGS data, performed segregation analysis and analysed the phenotype. AR, RM, RM, UA, AOC, GY, AS, GES and KS were involved in patient recruitment and clinical management. AR, RM and MS drafted the manuscript and all authors contributed to the manuscript. MS and HK conceived the study and MS, HK, MG, NH and JGG supervised the study. All authors read and approved the final manuscript.

  • Funding This work was supported by grants from the Simons Foundation for Autism Research #: 514863 National Institutes of Health R01NS048453 (to JGG), U54HG003067 to the Broad Institute and U54HG006504 to the Yale Center for Mendelian Disorders. JGG received support from Rady Children’s Institute for Genomic Medicine. MS acknowledges funding from Radboudumc and RIMLS Nijmegen (Hypatia tenure track fellowship), the ‘Deutsche Forschungsgemeinschaft’ (DFG, CRC1140 (KIDGEM)) and the European Research Council (ERC StG TREATCilia, grant No. 716344). HK acknowledges funding from ERAnet consortium, CRANIRARE2 (TUBİTAK SBAG-112S398), Yale Center for Mendelian Disorders (U54HG006504 to MG) and the Gregory M. Kiez and Mehmet Kutman Foundation (MG).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the Istanbul Koc University with the approval of the Institutional Ethics Review Board (approval number KUSoM; 2015.120.IRB2.047 CRANIRARE-2,HIC # 94060007680).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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