SCANNING GENES TO FIND CAUSE OF CHILD'S DISEASE
Audrey Lapidus adored
her baby's sunny smile and irresistible dimples, but grew worried when Calvin
did not roll over or crawl by 10 months and suffered chronic digestive
problems. Four neurologists dismissed his symptoms and a battery of tests
proved inconclusive. Desperate for answers, Audrey and her husband agreed to
have their son become UCLA's first patient to undergo a powerful new test
called exome sequencing.
Using DNA collected
from Calvin's and his parents' blood, a sophisticated sequencing machine
rapidly scanned the boy's genome, compared it to his parents' and flagged a
variant on his 18th chromosome. Calvin was diagnosed with Pitt-Hopkins
Syndrome, a rare genetic disorder affecting only 250 children worldwide. At
last Audrey and her husband had a concrete diagnosis and clear direction for
seeking the best treatment for their son.
Now a landmark UCLA
study makes a persuasive argument for the routine clinical use of exome
sequencing as a valuable tool for diagnosing children like Calvin with rare
genetic disorders. Published in the Oct. 18 online edition of the Journal
of the American Medical Association, the findings show that exome
sequencing produced a definitive diagnosis in 40 percent of UCLA's most complex
cases -- a quantum leap from the field's 5-percent success rate two decades
ago.
"Our study is the
first to show that sequencing a child's genome together with his or her
parents' dramatically improves geneticists' ability to reach a firm diagnosis
in rare disorders," said corresponding author Dr. Stan Nelson, vice chair
of human genetics and a professor of pathology and laboratory medicine at David
Geffen School of Medicine at UCLA. "We discovered a genetic cause for the
conditions affecting 40 percent of the hundreds of young children who come to
UCLA for exome sequencing due to developmental delays or intellectual disabilities."
The UCLA Clinical
Genomics Center was established in 2011 as one of three facilities in the world
(including Baylor and Harvard) to put DNA sequencing to clinical use. Unlike
earlier diagnostics that study one gene at a time, this test rapidly sifts through
all of the 37-million base pairs in a person's 20,000 genes to tease out the
single DNA change causing a rare genetic disorder. It focuses on the exome, the
protein-coding portions of genes that account for only 1 percent of DNA but
nearly 85 percent of the glitches known to cause human diseases.
In this two-year
study, Nelson worked with first author Hane Lee, an assistant adjunct professor
of pathology, to sequence and analyze the exomes of 814 children whose symptoms
had baffled previous clinicians despite exhaustive genetic, biochemical and
imaging tests.
Here's how it worked.
The UCLA center funneled the raw data from sequencing the genomes of each child
and their parents through its informatics pipeline to identify variants from
the standard human genome. The average person's exome contains more than 20,000
variants, nearly all benign.
Next the team applied
a series of filters to the data based on the patient's family history and other
relevant aspects of his or her condition. The researchers hunted for all genes
and mutations linked by medical literature to the patient's symptoms. Finally
UCLA's Genomics Data Board, a multidisciplinary team of experts, reviewed the
findings to reach a diagnosis.
The typical turnaround
time is under eight weeks, though test results have been returned to physicians
within 10 days in medically urgent situations. With preauthorization, many
insurance providers cover the cost to sequence a child and both parents. If
not, the out-of-pocket fee runs $6,650.
Audrey Lapidus says
that having a diagnosis for Calvin "meant the world." A former
journalist, she investigated the disorder extensively, launched the
Pitt-Hopkins Research Foundation and helped raise $1 million to fund studies at
six universities. She is passionate about advocating exome sequencing to
parents and physicians, who often don't inform families that the test is
available.
Understanding the
origin of Calvin's disease also carried an emotional price. Pitt-Hopkins
Syndrome can cause delayed intellectual development, motor delays, breathing
problems and seizures. Now an adorable 3-year-old, Calvin still cannot walk and
may never speak. Still, Lapidus and her husband would rather know what to
expect for their son and plan ahead than continue living in diagnostic limbo.
"All families
deserve a clear diagnosis of their child's condition," said Dr. Wayne
Grody, director of the UCLA Clinical Genomics Center and a professor of
pathology, human genetics and pediatrics at the David Geffen School of Medicine
at UCLA and Mattel Children's Hospital UCLA. "Exome sequencing plays an
important role in identifying the precise cause of a child's illness. This is
immediately useful to families and physicians in understanding how the disease
occurred, preventing unnecessary testing, and developing the best strategies to
treat it."
The Clinical Genomics
Center provides extensive pre- and post-test genetic counseling to guide
families through the tests and prepare them for the results. The team also
coordinates multidisciplinary care with UCLA specialists to address the medical
complications associated with each child's illness.
"Many parents of
a child with a genetic disorder postpone getting pregnant for fear of having a
child with the same disease," said Naghmeh Dorrani, genetic counselor.
"Exome sequencing can ease this concern by helping us to identify the risk
of recurrence and offer parents appropriate prenatal testing options."
"Many parents of
a child with a genetic disorder postpone getting pregnant for fear of passing
the same disease on to future children," said Naghmeh Dorrani, UCLA
genetic counselor. "Exome sequencing can ease this concern by helping us
to identify the risk of recurrence and offer parents appropriate prenatal
testing options."
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