title: A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.
abstract: 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.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Tham
authors.affiliation: Experimental Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Eklund
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Hammarsjö
authors.affiliation: Department of Clinical Chemistry, part of University Health Care in Region Skåne, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Bengtson
authors.affiliation: Department of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Geiberger
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lagerstedt-Robinson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Malmgren
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gintautas
authors.initials: G
authors.lastname: Grigelionis
authors.affiliation: Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.|Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Conner
authors.affiliation: Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.|Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lindgren
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
authors.affiliation: Department of Neuropediatrics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Albåge
authors.affiliation: Experimental Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zielinska
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Section for Perinatal Pathology, Department of Pathology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nikos
authors.initials: N
authors.lastname: Papadogiannakis
authors.affiliation: Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000503:physiopathology; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D055028:Comparative Genomic Hybridization; D059472:Exome / Q000235:genetics*; D005260:Female; D006031:Glycosylation; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000235:genetics* / Q000503:physiopathology; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D017423:Sequence Analysis, RNA
chemical_list: D008565:Membrane Proteins; D020033:Protein Isoforms; C469962:ALG9 protein, human; D008364:Mannosyltransferases