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.
- 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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