www.clinicalomics.com November/December 2017 Clinical OMICs 17
percent) of the 42 newborns received
a diagnosis after genome analysis, of
which 13 obtained a change in dis-
ease management. Overall, 11 (24 per-
cent) of NICU newborns sequenced
received a change in outcome.
"These are remarkable findings that
are going to change the way medi-
cine is practiced in the NICU," said
Kingsmore.
"This [approach] is still not well
advertised, well known or well
implemented in children's hospitals
around the world," Kingsmore said.
"We believe this will become a para-
digm for treating children around the
world."
Kingsmore described a recent suc-
cessful outcome in a case known as
Infant 6041. A two-day-old baby girl
named Sebastiana experienced seizures
beginning just 16 hours after delivery.
Standard drugs were ineffective or
required such high doses that the baby
was lethargic and couldn't feed.
Within 68 hours, Kingsmore's team
had reached a diagnosis of Ohtahara
syndrome, having discovered a de novo
missense mutation in a gene encod-
ing a potassium
channel, KCNQ2. A
change in treatment
resulted in control
over the seizures,
and Sebastiana was
discharged 18 days
after admission. A similar case at the
hospital had been admitted a year
earlier; but without the full genome
analysis, it took doctors two months
to reach the same diagnosis, and the
patient in that case has major brain
damage. Moreover, the reduced time
to Sebastiana's diagnosis resulted in
cost savings of about $180,000.
Enter the NovaSeq
While the current Rady pipeline is
among the most efficient in the world,
there is room for improvement. "The
HiSeq 2500 does a beautiful job,"
Kingsmore said, "but it only runs
one sample at a time and it is rather
costly."
Rady has just validated the Nova-
Seq instrument, placing it into clin-
ical (CLIA/CAP) production earlier
this month. "Almost everything is
different about the platform," King-
smore said. Initial results on 52 whole
genomes sequenced showed excellent
coverage of the entire genome (compa-
rable to the HiSeq) including known
Mendelian disease genes. Kingsmore
said he favors the 2x100-nucleotide
(compared to 2x150) approach, which
he says saves a lot of time.
Kinsgmore believes in 40x coverage
for newborn screening. "That's our
clinical specification," he said, adding
that the NovaSeq offers "an exqui-
sitively sensitive and specific test."
Whereas the HiSeq 2500 produced a
single human genome (at 40x cover-
age) over about 26 hours, requiring
two flow cells, the NovaSeq can gener-
ate six genomes (also 40x) in a 24-hour
run on a single flow-cell, for a third of
the cost of the HiSeq.
Kingsmore's groundbreaking work
was recently profiled in TIME maga-
zine in a story by Alice Park. He had
hoped to announce an even shorter
turnaround time, using a new tech-
nology that would prepare the DNA
library directly from a blood sample
without having to extract the DNA as
an intermediate step. But that tech-
nique wasn't ready in time.
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"Very few doctors have the in-depth genetics
training and deep knowledge of sequencing and
interpreting disease-causing variants."
—Martin Reese, CEO, Farbric Genomics
Fast, whole-genome sequencing is vital to helping the sickest babies born with a rare diesease.