MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive c erebellar, o cular, cranio f acial and g enital features (COFG syndrome)
- J Med Genet. 2019 May;56(5):332-339. doi: 10.1136/jmedgenet-2018-105623.
- 1. Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands.
- 2. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
- 3. Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, Istanbul, Turkey.
- 4. Inova Cardiovascular Genomics Clinic, Inova Translational Medicine Institute, Falls Church, Virginia, USA.
- 5. Genetics and Molecular Cell Sciences Research Centre, St George's, University of London, London, UK.
- 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. Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
- 8. Medical Genetics Department, Bilim University School of Medicine, İstanbul, Turkey.
- 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. Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
- 11. Medical Genetics Department, Bezmi Alem University School of Medicine, Istanbul, Turkey.
- 12. Paediatric and Genetic Counselling Center, Kerman Welfare Organization, Kerman, Iran.
- 13. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
- 14. Department of Medical Genetics, Kerman University of Medical Sciences, Kerman, Iran.
- 15. Centogene AG, Rostock, Germany.
- 16. Pediatrics Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany.
- 17. Medical Genetics Department, Koç University School of Medicine (KUSoM), İstanbul, Turkey.
- # Contributed equally.
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.