ArticleBMC medical genomics2014
"Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline.
Article in BMC medical genomics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
6 citing papers in PubMed, 7 citations in OpenAlex.
- Variant profile of Brazilian patients with Sanfilippo syndrome type B.Genetics and molecular biology · 2026Article
- Fine-tuning large language models for rare disease concept normalization.Journal of the American Medical Informatics Association : JAMIA · 2024Article
- Fine-tuning Large Language Models for Rare Disease Concept Normalization.bioRxiv : the preprint server for biology · 2024Article
- Review
- Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes.American journal of human genetics · 2018Article
- SeqMule: automated pipeline for analysis of human exome/genome sequencing data.Scientific reports · 2015Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundIn 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.
methodsInitial 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.
resultsExome 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.
conclusionsSuccessful 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.