2. Academic Validation
  3. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive c erebellar, o cular, cranio f acial and g enital features (COFG syndrome)

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.
Abolfazl Rad # 1 2,  Umut Altunoglu # 3,  Rebecca Miller # 4,  Reza Maroofian # 5,  Kiely N James 6,  Ahmet Okay Çağlayan 7 8,  Maryam Najafi 1,  Valentina Stanley 6,  Rose-Mary Boustany 9 10,  Gözde Yeşil 11,  Afsaneh Sahebzamani 12,  Gülhan Ercan-Sencicek 7,  Kolsoum Saeidi 13 14,  Kaman Wu 1,  Peter Bauer 15,  Zeineb Bakey 1 16,  Joseph G Gleeson 6,  Natalie Hauser # 4,  Murat Gunel # 7,  Hulya Kayserili # 3 17,  Miriam Schmidts # 1 16
Affiliations

Affiliations

  • 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.
PMID: 30487245 DOI: 10.1136/jmedgenet-2018-105623
Abstract

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.

Keywords

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

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