Mendelian Disorders(单基因病)

1000 Mendelian

Disorders Project

This paper published in Brain journal on November, 2011. TGM6 was identified as a novel spinocerebellar ataxias (SCA) causative gene with the collaboration of BGI, Xiangya Hospital, and Central South University. In this case, four patients from a

Chinese four-generation spinocerebellar ataxia family were sequenced to a mean

depth of 65.1X per individual. Exome sequences were enriched with NimbleGen 2.1M Human Exome Array. This finding of TGM6

as a novel causative gene of SCA

illustrates that next-generation

sequencing technologies

could been

successfully used for causative gene identification in Mendelian disorders.

This paper published in Journal of Investigative Dermatology on March 24, 2011. NCSTN reverse gene mutation was verified that it can lead to the occurrence of

acne. Two affected and an unaffected individual from a four-generation Chinese family were sequenced at a mean depth of 50X per individual. Exome sequences were enriched with Agilent SureSelect Human All Exon Kit. It is another important achievement of exome sequencing, by which

NCSTN gene mutation had been found out, represents a great significance to the diagnosis and treatment of reverse acne.

This paper published in PLoS Genetics on June 9, 2011. Mutations in zinc finger protein 644 isoform 1 (ZNF644) were identified as potentially responsible for the phenotype of high myopia with the collaboration of BGI and Sichuan Provincial People’s Hospital. Two high myopia infected individuals from a Han Chinese family were sequenced at a mean depth of 30X per individual. Exome sequences were enriched with NimbleGen 2.1M HD array. The results suggest that ZNF644 might be a causal gene for high myopia in monogenic form.

Case Sharing

NGS-based researches for Mendelian disorders in BGI Premier Scientific Partner / Contact Us

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Exome sequencing

There have been more than 80 papers published in top magazines since 2009. It indicates Next Generation Sequencing is an advanced and extremely cost-effective approach to identify Mendelian disorders’ genetic basis ，which will improve our understanding of the mechanisms, biological pathways and potential therapeutic targets.

Mendelian disorders, the so-called Monogenic diseases, are caused by single gene mutations in human genome. The mutation can either occur on a single chromosome or a pair of homologous chromosomes. So far, about 5000 Mende-lian disorders have been found in human. Most rare diseases are Mendelian disorders, which usually chronically debili-tating or even life-threatening, cause significant impact on the life quality of affected patients (of whom, many are children) and their family. Since, the diagnostic and therapeutic options for rare diseases is still barely available.Recent advances in Next-generation Sequencing technology and drastic reduction in its cost has been revolutionizing the Mendelian disorders research through identify of novel causative genes from a very small number of patients, some-times as few as one. Powered by over 164 Next-generation Sequencing platforms and over 1000 bioinformatics profes-sionals, BGI launched the “1000 Mendelian Disorders Project ” in May 2010. With this initiative, we seek to understand the molecular basis of key Mendelian disorders to facilitate their early prediction, diagnosis and identification of potential interventions.

In the research of Mendelian disorders, the experiment is based on the next generation sequencing technology and bioinformatics. Our workflow includes the following steps: library construction, exome capture, sequencing, standard analysis with variant calling and screen candidate causative genes . Generally, it will take us 60 working days(sample size ≤ 25).

Most disease-related or trait-related variations are located within exons.Able to capture both common and rare variants.

Achieve highly cost-effective results with rapid turnaround time.

Whole Genome Sequencing

Detect variations at whole genome level.

Identify causative genes that are not located on exome.

The genetic variations such as SNP, Indel, SV and CNV can be obtained.

Target Region Sequencing

Capture the intron and intergenic region in target region.Substantially narrow the sequencing region.

Validation suggestion

International Progress——NGS-Based Papers

NGS-based papers published worldwide

Overview

Strategy

Workflow Step 1

Examine candidate

muta ti ons in same family using Sanger sequencing or genotyping chip, check

presence of co-segrega ti on of genotypes and phenotypes

Step 2

Examine found AA-changing muta ti ons in all exons of genes validated in Step 1 in more unrelated pa ti ents by Sanger sequencing Step 3

Examine muta ti ons validated in Step 1 and Step 2using Sanger sequencing or

genotyping chip in more than 100 normal people