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J Med Genet. 2019 May;56(5):332-339. doi: 10.1136/jmedgenet-2018-105623. Epub 2018 Nov 28.

MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome).

Author information

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

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

PMID:
30487245
DOI:
10.1136/jmedgenet-2018-105623
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Conflict of interest statement

Competing interests: None declared.

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