541towards the development of appropriate models of good practice in the care of
patients and their families.
Monogenic diseases are frequent causes of neonatal morbidity and mortality, and
disease presentations are often undifferentiated at birth. Faulty genes for more than
~3,500 monogenic diseases out of the ~7,500 known genetic diseases have been
characterized, but clinical testing is available for only some of them and many fea-
ture clinical and genetic heterogeneity. Treatment is available for only ~500 of
these. Hence, an immense unmet need exists for improved molecular diagnosis in
infants. Approximately 1 in 20 babies in newborn intensive care units has a genetic
disease, which is diffi cult to diagnose. Because disease progression is extremely
rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly
to be relevant for clinical decision-making. A 50-h differential diagnosis of genetic
disorders by WGS has been described that features automated bioinformatic analy-
sis and is intended to be a prototype for use in neonatal intensive care units (Saunders
et al. 2012 ). Retrospective 50-h WGS identifi ed known molecular diagnoses in two
children. Prospective WGS disclosed potential molecular diagnosis of a severe
GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity
and multifocal seizure syndrome in another infant; identifi ed BCL9L as a novel,
recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known can-
didate genes in one infant. Sequencing of parents or affected siblings expedited the
identifi cation of disease genes in prospective cases. With the new method, a com-
puter program searches for genes based on the baby’s symptoms. Because it focuses
only on genes that cause diseases in newborns, it avoids the ethical problem of fi nd-
ings that are unrelated to the problem at hand. Thus, rapid WGS can potentially
broaden and foreshorten differential diagnosis, resulting in fewer empirical treat-
ments and faster progression to genetic and prognostic counseling. The method is
expensive, though, costing about $13,500. It is not yet covered by insurance.
Illumina has a new sequencer that could sequence DNA in 25 h and it will further
reduce the time for sequencing.
In the next 5 years, advances in sequencing technology will enable affordable
sequencing of the genomes of the four million infants born each year in the US
alone, which sequences will serve as a universal and complete genetic test to be
used throughout individuals’ lives to improve their development and help them lead
healthier lives. As such, a newborn’s sequence should ideally be obtained as early
as possible to reduce potential health and developmental risks. However, personal
genomic information will be useful only to the extent that the associations between
the genetic sequence and diagnosis or prognosis of a disease can be accurately made
in large numbers of people. Most of these association studies have yet to be carried
out, but one can foresee that improved diagnostic and prognostic methods would
lead to superior health economics and patient outcomes, despite the likelihood of
fi nding a “healthy” genome in the majority of newborns. Alternatively, ignoring the
genetic indicators of potential disease risk would almost certainly result in much
higher costs, not only for patients but also for governments or insurance companies
as compared to the cost of sequencing and analyzing a genome. With a positive
healthcare economics rationale, governments or insurance companies will choose to
pay for genomic sequencing as health-screening.
Sequencing in Genetic Disorders