543individuals with hypertriglyceridemia, compared to variants in controls, corre-
sponding to a carrier frequency of 28.1 % of affected individuals and 15.3 % of
controls. Consideration of rare variants in these genes incrementally increased the
proportion of genetic variation contributing to hypertriglyceridemia.
Discovery of the Gene for Miller Syndrome
WES has been applied successfully to discover the gene for a rare mendelian disor-
der of unknown cause, Miller syndrome, which is characterized by an under-sized
jaw, droopy eyes, cleft lip or palate, incomplete or unusual limb development (Ng
et al. 2009 ). The study identifi ed a single candidate gene, DHODH, which encodes
a key enzyme in the pyrimidine de novo biosynthesis pathway. Exome sequencing
of a small number of unrelated affected individuals is a powerful, effi cient strategy
for identifying the genes underlying rare mendelian disorders and will likely trans-
form the genetic analysis of monogenic traits. The unique value of complete genome
sequencing in families was demonstrated by results of another study to identify
mutations underlying Miller syndrome and ciliary dyskinesia, an inherited lung dis-
order in two affected siblings and their parents (Roach et al. 2010 ). Along with the
disease-related mutations that were detected, the study was also able to use the fam-
ily’s genome sequences to begin exploring the DNA mutation rate from one genera-
tion to the next. It is now possible to see all the genetic variations, including rare
ones, and to construct the inheritance of every piece of the chromosomes, which is
critical for understanding the traits that are important in health as well as disease.
Thus the analysis of a family’s genome can aid in the diagnosis and treatment of
individual family members. It is possible that family’s genome sequence may
become a part of an individual’s medical records in the future.
Personalized Cell and Gene Therapies of Genetic Disorders
Personalized biological therapies were described in Chap. 9. This chapter will
include brief description of applications of personalized cell and gene therapies in
some genetic disorders.
Personalized Stem Cell Transplant for Sickle Cell Anemia
Sickle cell anemia (SCA) is an inherited disorder of β-globin, resulting in red
blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expec-
tancy. There are anecdotal reports of successful use of UCB stem cells transplant
therapy of children suffering from SCD. Although myeloablative allogeneic
HSC transplantation is curative in children with SCD, the procedure is unduly
toxic in adults. Graft rejection and GVHD are additional barriers to its success.
Personalized Cell and Gene Therapies of Genetic Disorders