Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth Neuropathy

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N Engl J Med. 2010 Mar 10.

Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth Neuropathy.

Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L,

Bainbridge M, Dinh H, Jing C, Wheeler DA, McGuire AL, Zhang F, Stankiewicz P,

Halperin JJ, Yang C, Gehman C, Guo D, Irikat RK, Tom W, Fantin NJ, Muzny DM,

Gibbs RA.

From the Department of Molecular and Human Genetics (J.R.L., J.G.R., C.G.-J.,

M.B., F.Z., P.S., D.M.M., R.A.G.), the Human Genome Sequencing Center (J.G.R.,

D.R.D., D.C.Y.C., L.N., M.B., H.D., C.J., D.A.W., D.M.M., R.A.G.), the Center

for Medical Ethics and Health Policy (A.L.M.), the Department of Pediatrics

(J.R.L.), and Texas Children's Hospital (J.R.L.) - all at Baylor College of

Medicine, Houston; Atlantic Neuroscience Institute, Summit, NJ, and Mount Sinai

School of Medicine, New York (J.J.H.); and Life Technologies, Carlsbad, CA

(C.Y., C.G., D.G., R.K.I., W.T., N.J.F.). This article (10.1056/NEJMoa0908094)

was published on March 10, 2010, at NEJM.org.

BACKGROUND: Whole-genome sequencing may revolutionize medical diagnostics

through rapid identification of alleles that cause disease. However, even in

cases with simple patterns of inheritance and unambiguous diagnoses, the

relationship between disease phenotypes and their corresponding genetic changes

can be complicated. Comprehensive diagnostic assays must therefore identify all

possible DNA changes in each haplotype and determine which are responsible for

the underlying disorder. The high number of rare, heterogeneous mutations

present in all humans and the paucity of known functional variants in more than

90% of annotated genes make this challenge particularly difficult. Thus, the

identification of the molecular basis of a genetic disease by means of

whole-genome sequencing has remained elusive. We therefore aimed to assess the

usefulness of human whole-genome sequencing for genetic diagnosis in a patient

with Charcot-Marie-Tooth disease.

METHODS: We identified a family with a recessive form of Charcot-Marie-Tooth

disease for which the genetic basis had not been identified. We sequenced the

whole genome of the proband, identified all potential functional variants in

genes likely to be related to the disease, and genotyped these variants in the

affected family members.

RESULTS: We identified and validated compound, heterozygous, causative alleles

in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two

mutations, in the proband and in family members affected by Charcot-Marie-Tooth

disease. Separate subclinical phenotypes segregated independently with each of

the two mutations; heterozygous mutations confer susceptibility to neuropathy,

including the carpal tunnel syndrome.

CONCLUSIONS: As shown in this study of a family with Charcot-Marie-Tooth

disease, whole-genome sequencing can identify clinically relevant variants and

provide diagnostic information to inform the care of patients.

[Guest guest]

Hello All,

This is only the tiny tip of the iceberg as far as I can see. What

bothers me is two simple questions that this discovery portends.

#1. What about the variety and degree of symptoms, or phenotype if you

want, that we already have seen produced by these genetic atypical

configurations? The genome definition ONLY gives rise to a PROPENSITY for a

resultant disease. The results over a lifetime denotes the cost in

dollars and activity.

#2. Who is to say or predict the results to any individual? I feel a

bunch of medical labels coming to be attached to my social security

number that will determine what I can work at and how much my health

insurance is going to cost.

ly, this look at the future scares me a lot in terms of the

remaining few years of my life and more so for the lives of my children

and grandchildren. Of course we shouldn't stop exploring and

understanding the underpinning of these diseases for the good of those

who have to live with them and for the possibility of correcting the

flaws before the symptoms set in. But, we have a huge task ahead to

prevent the callous decent into a " Brave New World " culture that such

divination engenders!

EdM from NH

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