Introduction to NGS-based Clinical Diagnosis From NGS Data to
Clinical Diagnosis: A Hands-on Wokshop Berlin, April 9 th 10 th,
2014 Thomas F. Wienker ([email protected]) Max-Planck-Institute
for Molecular Genetics, Berlin-Dahlem
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NGS next generation sequencing Camille Flammarion, LAtmosphre.
Mtorologique populaire; Paris 1888
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as Genetics.
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Diagnostics at the genetic level: Finding and Characterization
of DNA-Sequencevariants
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... there is no better way to advance the proper practice of
medicine than to give our minds to the discovery of the usual laws
of nature by careful investigation of cases of rarer forms of
diseases. William Harvey (15781657) in a letter to the physician
Jan Vlackfeld Haarlem, Netherlands, April 24 th, 1657 cf. Groft SC
and Posada M (2010) in: Rare Disease Epidemiology, chpt. 1 Adv.
Exp. Med. Biol. Vol. 686, pp. 3 14
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NGS next generation sequencing WGS whole genome sequencing WES
whole exome sequencing PES partial exome sequencing panel
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WES whole exome sequencing WEA whole exome analysis WGS whole
genome sequencing TES targeted exome sequencing WGA whole genome
analysis TEA targeted exome analysis all disease genes, ca. 3200
4800, e.g. HPO-panel, ca. 2800 genes selected disease genes e.g.
Kingsmore-panel, 525 oder 1222 genes NGS: Next Generation
Sequencing ca. 20,200 genes, total 50 70 Mbp ca. 3.1 10 9 bp
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THEMED ARTICLE Review The advent of next-generation sequencing
technologies has revolutionized the study of genetic variation in
the human genome. and variants detected in noncoding regions remain
largely uninterpretable. variants detected in noncoding regions
remain largely uninterpretable.
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Pedigree: M 90 00 029 Gene: TLR10 HGNC:15634 OMIM: 606270
Location: 4p14 Transcript(s):NM_001017388.2:c.734C>A
NM_001195106.1:c.734C>A NM_001195107.1:c.734C>A
NM_001195108.1:c.692C>A NM_030956.3:c.734C>A
NM_001017388.1:c.734C>A NM_030956.2:c.734C>A
Protein:NP_001017388.1(TLR10):p.S245X T/ T G /T Mutation: Genomic:
NC_000004.11:g.38,776,478G>T
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Database of Genomic Variantion There is no genetic diagnosis
(sensu strictu) outside the framework of the Mendelian paradigm cf.
Ken Weiss, TMF School extra, Berlin, 24. bis 28. September
2012
ACMG recommendations for standards for interpretation and
reporting of sequence variations: Revisions 2007 Genetics IN
Medicine, April 2008 Vol. 10 No. 4, 294 -300 1. Sequence variation
is previously reported and is a recognized cause of the disorder 2.
Sequence variation is previously unreported and is of the type
which is expected to cause the disorder 3. Sequence variation is
previously unreported and is of the type which may or may not be
causative of the disorder 4. Sequence variation is previously
unreported and is probably not causative of disease 5. Sequence
variation is previously reported and is a recognized neutral
variant 6. Sequence variation is not known or expected to be
causative of disease, but is found to be associated with a clinical
presentation
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Things should be made as simple as possible, but not
simpler.
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Thank You for attention! Feel free to ask questions!