Whole genome sequencing is being used for identifiying new disease-causing mutations for optimizing patient management in clinical settings. 

Sequencing targeted disease panels has yielded additional analytical and cost benefits. 

1. Preconception testing for recessive disease

2. Genetic testing for heritable ovarian and related cancers

NGS enables a much higher degree of perellelism than SAnger sequencing, which alllows for the accurate and highly multiplexed molecular testing of millions of nucleotides in hundresa of genes simultaneously

NGS also enables the use of much cmaller reaction volumes per DNA sample. 

Target gene enrichment refers to the lective capture of specific genomic regiona from a DNA sample prior to sequencing. 

Results in specific data that is much easier to analyze. 

more the 1100 mendelian recessive diseases have been identified in th epast three decades. 

large praction appear in early childhood with some being very severe and highly penetrant. 

Diagnosed with a cherry red spot on the retina. B. Sachs recognized the familial nature of the disease. 

Between ages 3 to 6 months the child shows progressive weakness, decreased motor skills, and decreased attentiveness. 

Reduction in vision and tracking, and exhibits the diagnostic cherry red spot. 

Progressive neurodegeneration, typically followed by seizures by age 2. 

Loss of motor function and cognitive function with death usually occuring before age 4. 

Caused by  mutation in the Hex-A gene on chromosome 15

Hexosaminidase A which catalyzes the breakdown of Gm2 ganglioside. 

Absence of functional hexosaminidase A, allows Gm2 ganliosides to accumulate causing progressive damage to the brain's neurons. (child stores 100 to 1000 times more Gm2 gangliosides in the brain than unaffected children.)

More than 100 mutations have been discovered in the Hex-A gene towards taysachs

Most common is the insertion of four nucleotides in exon 11 of the Hex-A gene

Insertion leads to an early stop codon and thus a lose of function

Ashkezani jews

Amish

Cajuns

Resulting from genetic drift assiciated with small fouding populations early in the etnic group's history. 

Success with tay sachs has led to implementation of preconseption genetic screening for other severe recessive childhood diseases

For ashkenazi jews genetic screening is recommended to 9 other diseases including canavan and gauacher disease that are also neurodegenerative

Diagnosed with Batten disease at age 5. 

MOst common form of agroup of diseases called neuronal ceroid lipofuscinose. (NCLs)

6-24 months = inantile

2-4 years = late infantile

4-10 years = juvenile

CLN1 for infantile

CLN2, CLN5, CLN6, or CLN7 for late infantile

CLN3 for juvenile

In each case, the mutaitons affect the funciton of enzymes normally invlovedin the breakdown of lipofusins

lipofuscins build up in neurons leading to neurodegenerative effects

Work to create a comprehensive diagnostic test for many to all recessive childhood diseases 

In January 2011 Kingsmore published diagnostic tests capable of assaying several hundred DNA samples simultaneously for 448 recessive childhood diseases. 

Include more than just neurological disorders and enables detection of a variety of mutation types. 

Effecitveness was tested across known genomes. 

Detected a total o 291 different mutations estimating the average individual was a carrier for 2.8 disease mutations. 

Detected new mutaitons where the variants are of unknown significance

verage individual was a carrier for about 11 VUS

Some will be identified as disease causing mutations. 

Kingsmore and colleagues expanded the test to include 592 childhood diseases

Expect to add 100-150 mendelian diseases in the next three years

By 2015 cost should be lowered to 200 dollars per individual. 

NGS and terget gene enrichment also is transforming other aspect of reproductive health care for women for heriable ovarian and related cancers

Ovarian cancer is the deadliest of reproductive carcinomas

Significant fraction of women developing ovarian cancer carry heritable mutations in the tumor suppressor genes BRCA1 and BRCA2

Mutations in BRCA1 result in lifetime risk of ovarian cancer of 50% while BRCA2 is 20%

Othe tumor receptor genes such as PALB2 and RAD51C also are linked to familial ovarian cancer. 

Tumor suppressor genes encode proteins that are negative regulator of the cell cycle. 

Mutations in the genes disable the regulatory function of the proteins, which in turn enables proliferation of the cancerous cells and growth of the malignant tumors. 

BRAC1 and BRAC2 increases lifetime risk of breast cancer and other cancers. 

Diagnostic test using target NGS in 21 tumor suppressor genes. 

The test detected a total of 85 germ line, loss-of-function mutations in 12 of the targeted 21 genes

Large fraction of the mutaitons were in either BRCA1 or BRCA2. 

The remaining 22 mutations were distributed across 10 other genes, including 6 genes that had not previously been impicated. 

They emphasize cost and soeed

Recently begun expanding the BROCA test to target colon, melanoma, and pancreatic cancers, thus providing a single NGS-based test capable of assessing gentic susceptibility to a broad array of cancers.