Abstract
Background
Biallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants.
Methods and results
We performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant’s fibroblasts to determine primary ciliary phenotype.
Results
We identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia.
Conclusion
Biallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants.
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Acknowledgements
The authors thank the Exome Aggregation Consortium Database; a full list of contributing groups can be found at http://exac.broadinstitute.org/about. The authors thank the Genotype-Tissue Expression (GTEx) Project, which was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 1 May 2018. This work was supported by grants from the National Institutes of Health (K08 HL105891 (J.A.W.), K12 HL120002 (F.S.C.), R21/33 HL120760 (F.S.C.)), R01 HL128370 (M.R.M.), the Eunice Kennedy Shriver National Institute of Child Health & Human Development (U54 HD087011 (J.S.S.), the Children’s Discovery Institute (F.S.C., J.A.W., M.R.M.), and the Saigh Foundation (F.S.C.).
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Conception and design: J.A.W., D.J.W., M.S., D.B., and F.S.C. Acquisition, analysis, or interpretation of data: J.A.W., D.J.W., P.Y., M.S., D.B., M.V.A., E.B., J.S.S., D.S., M.R.M., and F.S.C. Drafting and revising the manuscript for important intellectual content: J.A.W., D.J.W., P.Y., M.S., D.B., E.B., J.S.S., D.S., B.P.H., M.V.A., T.F., S.K.D., M.R.M., and F.S.C. All authors have approved the final version and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have seen and approved the submission and take full responsibility for the manuscript.
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Wambach, J.A., Wegner, D.J., Yang, P. et al. Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures. Pediatr Res 84, 435–441 (2018). https://doi.org/10.1038/s41390-018-0083-z
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DOI: https://doi.org/10.1038/s41390-018-0083-z
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