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Gillessen-Kaesbach–Nishimura Skeletal Dysplasia Due to Pathogenic Variants in ALG9

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Gillessen-Kaesbach–Nishimura Skeletal Dysplasia Due to Pathogenic Variants in ALG9 European Journal of Human Genetics (2016) 24, 198–207 & 2016 Macmillan Publishers Limited All rights reserved 1018-4813/16 www.nature.com/ejhg ARTICLE A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9 Emma Tham1,2,12, Erik A Eklund3,12, Anna Hammarsjö1,2,12, Per Bengtson4, Stefan Geiberger5, Kristina Lagerstedt-Robinson1,2, Helena Malmgren1,2, Daniel Nilsson1,2, Gintautas Grigelionis1, Peter Conner6,7, Peter Lindgren6,7, Anna Lindstrand1,2, Anna Wedell1,8, Margareta Albåge9, Katarzyna Zielinska3, Ann Nordgren1,2, Nikos Papadogiannakis10,12, Gen Nishimura11,12 and Giedre Grigelioniene*,1,2,12 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+2T4A 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 (2016) 24, 198–207; doi:10.1038/ejhg.2015.91; published online 13 May 2015 INTRODUCTION the endoplasmic reticulum (ER), is transferred to asparagine residues Fetal skeletal dysplasias encompass a diverse group of disorders and in the nascent polypeptide chain. CDG syndromes with disrupted the genetic causes are still unknown for a significant proportion of N-linked glycosylation are multisystem disorders with, for example, cases. A very rare lethal fetal syndrome with polycystic kidneys, typical intellectual disability, hypotonia, epilepsy, liver disease, coagulopathy, facial features and varying malformations, was first reported by hormonal dysfunction and cardiac disease.4 The severity varies greatly Gillessen-Kaesbach et al, while features of skeletal dysplasia in this from mild intellectual disability with normal lifespan to neonatal syndrome were characterized by Nishimura et al.1,2 Despite the lethality. Skeletal dysplasia is not a commonly recognized symptom of varying degree and combination of internal malformations and CDG syndromes but has been reported in rare patients.5 Of note, a dysmorphic features, the skeletal features of the patients were few patients with ALG3- and ALG12-CDG share some skeletal features strikingly uniform, including short tubular bones, deficient ossification with those described by Gillessen-Kaesbach et al and Nishimura of the cervical vertebral bodies and pubic rami, round pelvis, decreased et al.1,2,6–8 ossification of the frontoparietal bones, thickening of the occipital ALG9 encodes an alpha-1,2-mannosyltransferase that catalyzes two bones, ulnar deviation of the hands and short extremities.1,2 steps in the LLO biosynthesis. The biosynthesis starts on the cytosolic The congenital disorders of glycosylation (CDG) constitute a large side of the ER where a dolichol pyrophosphate-linked heptasaccharide 9 group of syndromes with disruption of one or several of the bio- (GlcNAc2Man5)isproduced. This structure is translocated to the synthetic pathways of complex glycans as a common denominator.3 luminal side of the ER where three different mannosyltransferases, VI Most CDG patients have a disruption in the N-linked pathway, in (ALG3), VII/IX (ALG9), and VIII (ALG12), sequentially add four which a lipid-linked precursor oligosaccharide (LLO), preformed in mannose residues to the LLO before three different glucosyltransferases 1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 2Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; 3Experimental Pediatrics, Clinical Sciences, Lund University, Lund, Sweden; 4Department of Clinical Chemistry, part of University Health Care in Region Skåne, Lund, Sweden; 5Department of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden; 6Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden; 7Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden; 8Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; 9Department of Neuropediatrics, Karolinska University Hospital, Stockholm, Sweden; 10Section for Perinatal Pathology, Department of Pathology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; 11Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan *Correspondence: Dr G Grigelioniene, Department of Molecular Medicine and Surgery; Clinical Genetics; and Center of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 76, Sweden. Tel: +46 8 5177 3926; Fax: +46 8 327734; E-mail: [email protected] 12These authors contributed equally to this work. Received 29 November 2014; Received 24 February 2015; accepted 31 March 2015; published online 13 May 2015 ALG9-CDG EThamet al 199 finalize the LLO with the addition of three glucose residues Autopsy and sampling for genetic and biochemical analyses (GlcNAc2Man9Glc3). ALG9 deficiency (ALG9-CDG) has been All fetal autopsies were performed at the Section for Perinatal Pathology at described in three patients with symptoms including intellectual Karolinska University Hospital in Huddinge. Skeletal surveys were performed fi disability, central hypotonia, microcephaly, epilepsy, pericardial effu- owing to suspected skeletal dysplasia. Autopsy ndings, clinical features and skeletal surveys of the three patients are summarized in Figures 1 and 2 and sion and renal cysts, but no skeletal dysplasia or visceral malforma- Tables 1 and 2. Routine examination of fetuses includes preservation of frozen 8,10,11 tions were noted. tissues. Spleen specimens from the patients and age-matched controls were In this report, we describe three patients with skeletal dysplasia, snap shot frozen at 80 °C at the autopsies and kept until analysis. Age-matched polycystic kidney and several multiple malformations, the pheno- control samples were collected from three fetuses without internal malforma- types highly similar to those first reported by Gillessen-Kaesbach tions (GA 21–22 weeks) examined owing to spontaneous abortions, whereas and Nishimura and somewhat overlapping with those of the normal spleen tissue from an adult was obtained at autopsy (approved by the individuals with ALG3- and ALG12-CDG.1,2,7,12 Our patients are Regional Ethical Committee, Lund University 2013/206). White blood cell RNA and serum from heterozygous parents and adult control individuals were used homozygous for a deleterious variant in the splice donor site of for cDNA and Trf glycosylation analyses, respectively. DNA and RNA were 4 exon 10 in ALG9 (NG_009210.1:g.35929T A also denoted extracted from frozen tissue samples of spleen and lungs from the patients and NM_024740.2:c.1173+2T4A). We show that this variant results from peripheral blood and saliva from the family members. in skipping of exon 10, leading to a shorter RNA with a frameshift, a premature stop codon and abnormal N-glycosylation pattern in Genetic investigations all the affected patients. Array-CGH, whole exome sequencing (WES) and Sanger sequencing.DNA Our study indicates that Gillessen-Kaesbach–Nishimura syndrome samples of patients 1 and 2 were screened for copy number variations using is caused by deleterious variants in the ALG9 gene, thus extending the array-CGH with a resolution of 50 kb in combination with a custom-designed high-resolution targeted array-CGH for 872 genes involved in skeletal phenotypic spectrum of ALG9-CDG. In combination with previously dysplasias, ciliary disorders and malformation syndromes (Agilent Technologies, reported similar features in few individuals with ALG3-CDG and Palo Alto, CA, USA). ALG12-CDG, it suggests that Gillessen-Kaesbach–Nishimura syn- WES was performed as a trio in family 1 and as a quartet in family 2 and drome belongs to the most severe end of the clinical spectrum data processing was performed at Oxford Genome Technologies (http://www. associated with N-glycosylation abnormalities. ogt.co.uk/). Briefly, paired end sequencing libraries were prepared according to the manufacturer's instruction (TruSeq, Illumina, San Diego, CA, USA), exonic PATIENTS AND METHODS
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