title: "Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline.
abstract: BACKGROUND
  In developing countries, many cases with rare neurological diseases remain undiagnosed due to limited diagnostic experience. We encountered a case in China where two siblings both began to develop idiopathic progressive cognitive decline starting from age six, and were suspected to have an undiagnosed neurological disease.
  
  
  METHODS
  Initial clinical assessments included review of medical history, comprehensive physical examination, genetic testing for metabolic diseases, blood tests and brain imaging. We performed exome sequencing with Agilent SureSelect exon capture and Illumina HiSeq2000 platform, followed by variant annotation and selection of rare, shared mutations that fit a recessive model of inheritance. To assess functional impacts of candidate variants, we performed extensive biochemical tests in blood and urine, and examined their possible roles by protein structure modeling.
  
  
  RESULTS
  Exome sequencing identified NAGLU as the most likely candidate gene with compound heterozygous mutations (chr17:40695717C > T and chr17:40693129A > G in hg19 coordinate), which were documented to be pathogenic. Sanger sequencing confirmed the recessive patterns of inheritance, leading to a genetic diagnosis of Sanfilippo syndrome (mucopolysaccharidosis IIIB). Biochemical tests confirmed the complete loss of activity of alpha-N-acetylglucosaminidase (encoded by NAGLU) in blood, as well as significantly elevated dermatan sulfate and heparan sulfate in urine. Structure modeling revealed the mechanism on how the two variants affect protein structural stability.
  
  
  CONCLUSIONS
  Successful diagnosis of a rare genetic disorder with an atypical phenotypic presentation confirmed that such "genotype-first" approaches can particularly succeed in areas of the world with insufficient medical genetics expertise and with cost-prohibitive in-depth phenotyping.
authors.affiliation: Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong, 510623, China. tlingshi@jnu.edu.cn.|Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, Guangdong, 510623, China. tlingshi@jnu.edu.cn.|GHM Collaboration and Innovation Center for Tissue Regeneration and Repair, Jinan University, Guangzhou, Guangdong, 510623, China. tlingshi@jnu.edu.cn.
authors.forename: Lingling
authors.initials: L
authors.lastname: Shi
authors.affiliation: Neonatal Intensive Care Unit, The 1st Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510623, China. 13710475291@163.com.
authors.forename: Bingxiao
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, 510623, China. xxhuang321@163.com.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Medical Imaging Center, The 1st Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510623, China. lingxuey@163.com.
authors.forename: Xueying
authors.initials: X
authors.lastname: Ling
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, 94305, USA. tianyunl@stanford.edu.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Liu
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11797, USA. glyon@cshl.edu.
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
authors.affiliation: Department of Neurology, The 1st Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510632, China. tlil@jnu.edu.cn.
authors.forename: Anding
authors.initials: A
authors.lastname: Xu
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, 90089, USA. kaiwang@usc.edu.|Department of Psychiatry & Behavioral Sciences, University of Southern California, Los Angeles, CA, 90089, USA. kaiwang@usc.edu.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
mesh_terms: D000118:Acetylglucosaminidase / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002681:China; D003072:Cognition Disorders / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation
chemical_list: C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase