clinical genetics - molmedmircea cretu stancu, …jeroen de ridder & wigard p. kloosterman...
TRANSCRIPT
Clinical Genetics Leading the way in genetic issues
Genomics 2040
Prof. Robert Hofstra
head department Clinical Genetics
I have:
-severe unexplained bowel problems
(immunological?)
(and arthritis)
I have been referred to an Gastroenterologist
in the Erasmus MC
Hofstra in 2040
I undergo several tests and scans during the day and by the
end of the day my gene passport is ready
It mentions all informative variants important for:
Chance on mono genic diseases
Complex traits
Carrier ship
Drug response
Therapy
Diet
Etc.
Gene passport
GenenPaspoort PASSPORT/PASSEPORT
Artificial Intelligence will be used to find out whether the
disease for which I come (after all kind of tests) can be linked
to variants in my DNA and whether there is any possible
treatment.
There is an multidisciplinary consultation including a clinical
geneticist (and myself)
you have a clear predisposition which fits
the clinical picture:
-referred to the gastroenterologist for
treatment
-referred to the dietitian
-referred to pharmacist to adjust medication
you have a strong predisposition to colon cancer
- referred to gastroenterologist for preventive therapy
Everyone who enters the hospital receives a gene passport
It will have information on rare and common diseases
The time path is very short
The data will also be important for the family of the patient
In 20 jaar
Fiction or reality?
GenenPaspoort PASSPORT/PASSEPORT
Common diseases
Common diseases
Common diseases
Common diseases
Farmacogenetica
Genetische variatie in het SLCO1B1 gen is geassocieerd met een verhoogd risico op statine-geïnduceerde myopathie
Farmacogenetica
Behandeling / Gentherapie
Dragerschapstesten
Dragerschapstesten
A gene passport in 20 years is NO fiction
Illumina
51nt (single end) shallow WGS (NIPT, pathology)
300bp (2x 151nt, paired end) – WES, WGS
3, 10, 30 kb mate-pair se – WGS for structural variation
10X using Illumina – WGS while haplotyping
PACBIO
10-15kb (up to ˜100kb)
Oxford– Nanopore
Size - depends on DNA extraction, cDNA synthesis
Standard DNA isolation kits: 10-30kb
New kits/other techniques >100kb
Long read sequencing
If the errors are truly random, increased coverage should be able to get
rid of these.
And that’s indeed (partially) the case.
Long Reads & Random errors
Structural variants that do not require base pair resolution
• Repeats (repeat expansions, sine/line, retrovirus)
• Structural variants (CNV, translocations, inversions)
• mRNA sequencing: alternative splicing
• mRNA sequencing: down stream pathways
Short-term use of Long read Seq
Telomere-to-telomere assembly of a complete human X chromosome
H. Miga, … Evan E. Eichler, …Adam M. Phillippy
https://www.biorxiv.org/content/10.1101/735928v3
Construction of a ∼2.8 megabase centromeric satellite DNA array closing all 29 remaining
gaps in the current reference
For the first time finishing the human genome is now within reach
Mapping and phasing of structural variation in patient genomes using nanopore
sequencing
Mircea Cretu Stancu, …Jeroen de Ridder & Wigard P. Kloosterman
Nature Communications (2017)
Nanopore to Promethion
Two papers on RNA-seq and diagnostic yield
Cummings et al. : Improving genetic diagnosis in Mendelian disease
with transcriptome sequencing
Sci Transl Med. 9: 386 (2017).
Kremer et al. : Genetic diagnosis of Mendelian disorders via RNA
sequencing
Nat Commun. 8:15824 (2017)
Summary
Techniqual improvements are still needed to move from exomes to
whole genomes
The most challenging aspect will be data interpretation of non-coding
sequences
We need to make automated reports from genomes
What do patients want to know?
Can we offer this as a preventive screen?
We need to talk to the general public about these fast changes in our
field
Policy makers need to get involved
