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A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.

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Author

  • Emma Tham
  • Erik A Eklund
  • Anna Hammarsjö
  • Per Bengtson
  • Stefan Geiberger
  • Kristina Lagerstedt-Robinson
  • Helena Malmgren
  • Daniel Nilsson
  • Gintautas Grigelionis
  • Peter Conner
  • Peter Lindgren
  • Anna Lindstrand
  • Anna Wedell
  • Margareta Albåge
  • Katarzyna Zielinska
  • Ann Nordgren
  • Nikos Papadogiannakis
  • Gen Nishimura
  • Giedre Grigelioniene
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Summary, in English

A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3- and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.91.

Publishing year

2015

Language

English

Publication/Series

European Journal of Human Genetics

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics

Status

Published

ISBN/ISSN/Other

  • ISSN: 1476-5438