title: Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans.
abstract: Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans.
authors.affiliation: Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Saudi Arabia. dralfadhelm@gmail.com.
authors.forename: Majid
authors.identifier: http://orcid.org/0000-0002-9427-7240
authors.initials: M
authors.lastname: Alfadhel
authors.affiliation: Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Saudi Arabia.
authors.forename: Marwan
authors.initials: M
authors.lastname: Nashabat
authors.affiliation: Medical Imaging Department, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Hanan Al
authors.initials: HA
authors.lastname: Qahtani
authors.affiliation: Department of Pediatrics, College of Medicine, Qassim University, Almulyda, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alfares
authors.affiliation: Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Saudi Arabia.
authors.forename: Fuad Al
authors.initials: FA
authors.lastname: Mutairi
authors.affiliation: Medical Imaging Department, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Hesham Al
authors.initials: HA
authors.lastname: Shaalan
authors.affiliation: GeneDx, Gaithersburg, MD, 20877, USA.
authors.forename: Ganka V
authors.initials: GV
authors.lastname: Douglas
authors.affiliation: Department of Pediatrics, Section of Genetics, The University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
authors.forename: Klaas
authors.initials: K
authors.lastname: Wierenga
authors.affiliation: GeneDx, Gaithersburg, MD, 20877, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: Neurology Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Muhammad Talal
authors.initials: MT
authors.lastname: Alrifai
authors.affiliation: Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan
authors.initials: F
authors.lastname: Alkuraya
authors.affiliation: GeneDx, Gaithersburg, MD, 20877, USA.
authors.forename: Qais Abu
authors.initials: QA
authors.lastname: Ali
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000235:genetics* / Q000473:pathology; D007223:Infant; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D014166:Transferases / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D050487:Glycine Plasma Membrane Transport Proteins; D009097:Multienzyme Complexes; C493268:SLC6A9 protein, human; C064525:glycine cleavage system; D000594:Amino Acid Oxidoreductases; D014166:Transferases; D005998:Glycine