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Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability

Journal of Human Genetics volume 65, pages 743–750 (2020)Cite this article

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Abstract

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.

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Acknowledgements

We are grateful to the patient and family for participating in this study, Sam Hawarden and David Markie for computational assistance. Glycomics measurements on the timsTOF Pro instrument were supported by the Dutch Organization for Scientific Research (NWO)—ZonMw Medium Investment grant number 9118025 and the Radboud University interfaculty grant for the Radboud Consortium for Glycoscience. RL was supported by a University of Otago Division of Health Sciences summer studentship. DJ is supported by the Neurological Foundation of New Zealand. KMK is supported by Marsden Fund and LSB is supported by a Rutherford Discovery Fellowship, both administered by the Royal Society of New Zealand.

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Authors and Affiliations

  1. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Karen M. Knapp, Rebecca Luu, Danielle Jenkins & Louise S. Bicknell

  2. Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, Netherlands

    Melissa Baerenfaenger & Dirk J. Lefeber

  3. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands

    Fokje Zijlstra, Hans J. C. T. Wessels & Dirk J. Lefeber

  4. Genetic Health Services New Zealand, Wellington, New Zealand

    Katherine Neas

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  1. Karen M. Knapp
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Correspondence to Louise S. Bicknell.

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This study has ethics approval from the New Zealand Heath and Disability Ethics Committee (16/STH/3). Informed consent was obtained for participation in the genetics study and separate consent was granted for the publication of photos.

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Knapp, K.M., Luu, R., Baerenfaenger, M. et al. Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability. J Hum Genet 65, 743–750 (2020). https://doi.org/10.1038/s10038-020-0764-4

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