"Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline

Shi, L, Li, Bingbin, Huang, Y., Liu, T, Lyon, Gholson J., Xu, A, Wang, Kai (2014) "Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline. BMC Med Genomics, 7 (1). p. 66.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/25466957
DOI: 10.1186/s12920-014-0066-9


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.

Item Type: Paper
Subjects: bioinformatics
bioinformatics > genomics and proteomics
CSHL Authors:
Communities: CSHL labs > Lyon lab
Depositing User: Andrea Potopsingh
Date: 2014
Date Deposited: 12 Jan 2015 20:07
Last Modified: 12 Jan 2015 20:07
PMCID: PMC4267425
Related URLs:
URI: https://repository.cshl.edu/id/eprint/31118

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