Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix.

Center for Molecular and Biomolecular Informatics Radboud Institute for Molecular Life Sciences Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Centre for Inherited Metabolic Disease Evelina Children's Hospital Guys and St Thomas NHS Foundation Trust London SE1 7EH UK

CNRS UMR 8576 Structural and Functional Glycobiology Unit FRABIO University of Lille 59655 Villeneuve d'Ascq France

Department of Child Health University Hospital of Wales Cardiff UK

Department of Child Neurology University Hospital Stavanger Stavanger Norway

Department of Clinical Chemistry VU University Medical Center Amsterdam The Netherlands

Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands

Department of Enzymology and Cellular Function Institute of Child Health Athens Greece

Department of Genetics University Medical Center Utrecht Utrecht The Netherlands

Department of Human Genetics Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Department of Medical Biochemistry Oslo University Hospital and Faculty of Medicine Institute of Clinical Medicine University of Oslo Oslo Norway

Department of Medicine Physiology and Institute of Medical Science Faculty of Medicine University of Toronto ON Canada

Department of Metabolic Diseases University Medical Center Utrecht Utrecht The Netherlands

Department of Neurology Donders Institute for Brain Cognition and Behavior Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Department of Paediatrics Tawam Hospital Al Ain UAE

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Department of Tumor Immunology Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Division of Metabolic Diseases Beatrix Children's Hospital University Medical Center Groningen PO BOX 30 001 9700 RB Groningen The Netherlands

Genetics and Rare Diseases Research Division Bambino Gesù Children's Research Hospital Rome Italy

King Abdullah International Medical Research Centre King Saud bin Abdul Aziz University for Health Sciences Division of Genetics Department of Pediatrics King Abdullah Specialized Children Hospital King Abdul Aziz Medical City Ministry of National Guard Health Affairs Riyadh Saudi Arabia

NIZO 6710 BA Ede The Netherlands

NSW Biochemical Genetics Service The Children's Hospital at Westmead Disciplines of Genetic Medicine and Child and Adolescent Health The University of Sydney NSW 2145 Australia

Radboud Center for Mitochondrial Disorders Translational Metabolic Laboratory Department of Pediatrics Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Translational Metabolic Laboratory Department Laboratory Medicine Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Zebrafish Centre for Advanced Drug Discovery and Keenan Research Centre for Biomedical Science Li Ka Shing Knowledge Institute St Michael's Hospital Toronto ON Canada

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