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When should my patients have
their genome sequenced?
BY DAVID P. BICK, MD
David P. Bick, MD, is a geneticist and medical director of Genetics at Children’s
Hospital of Wisconsin. He also is a professor and chief of Genetics at the Medical
College of Wisconsin.
The sequence of the human
genome was established in 2000
after a 10-year effort at a cost
of $3 billion. Over the last three
years, the cost of sequencing
an individual has dropped
dramatically. As a result, genome
sequencing is now used in the
care of patients at Children’s
Hospital of Wisconsin.
A GENOME PRIMER
The nucleus of every somatic
human cell contains a complete
set of genes, the instructions that
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determine all of our features such as eye color and hair color. Genes work by instructing cells
to make proteins; it is the proteins that carry out the functions of the cell. Change in genes
cause genetic disorders. For example, changes in one gene give rise to cystic fibrosis (CFTR)
while changes in other genes can result in breast and ovarian cancer (BRCA1) or affect drug
metabolism (CYP2C9). In humans, there are about 20,000 genes. Gene changes that do not
have medical consequences are called benign variants. Changes that give rise to disease
are called pathogenic variants. When there is a change where the clinical consequences
are not understood it is called a variant of uncertain significance (VUS). This variant
classification is used in DNA-testing laboratory reports.
Genes are composed of deoxyribonucleic acid (DNA), and DNA is composed of four
different nucleotides – A, C, G and T. A particular sequence of these four letters makes
up each gene. The different genes are strung together as long DNA molecules called
chromosomes. There are about 6 billion letters, often called base pairs, which compose the
46 chromosomes in a human cell. Taken together, these 6 billion base pairs of DNA make up
the genome.
It is important to note that only a portion of the genome’s 6 billion base pairs encode genes,
and that only a portion of each gene codes for a protein. The parts of the gene that code
for the protein are called coding sequence. These coding portions are found in the exons of
genes. The exons (together called the exome) make up only 1 percent of the genome. More
is known about the exome than about the rest of the genome, therefore testing focuses on
coding sequence.
WHO SHOULD HAVE GENOME SEQUENCING?
Genome sequencing is used most frequently when families and their providers have
exhausted other approaches (often over many years) to finding a diagnosis for a child’s
illness. Ending this diagnostic odyssey has obvious clinical and economic advantages.
There are several steps that physicians can take to improve the chance of success with
genome sequencing:
1. P
atients should have an evaluation by physicians with expertise in the patient’s condition.
These reports help the laboratory correlate the patient’s phenotype and family history with
the genotype derived from sequencing.
2. Confirmation that the patient has had the current standard diagnostic testing used to
evaluate that patient’s phenotype. This ensures that the most cost-effective approach to
diagnosis has been taken.
3. F ocus on patients with an apparently undiagnosed monogenic genetic disorder, ideally
with a rare or distinctive phenotype.
4. Focus on cases where a molecular diagnosis could help physicians and families with
medical decision-making and management, such as treatment and family planning. This
is an important part of securing insurance preauthorization.
5. S election of cases with appropriate samples available to carry out initial genomic
sequencing as well as additional testing, including confirmatory functional assays in the
patient and segregation analysis of variants in the parents and other family members.
6. F avorable comparison of the cost of genomic sequencing versus testing individual genes
for the phenotype in question.
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Physician Referral and Consultation (800) 266-0366
THE FUTURE
The use of genome sequencing in cases where families have been on a diagnostic odyssey
is only the first use of this revolutionary technology. Its use as a diagnostic tool in cancer is
an obvious next step. By comparing the genome of a cancer with the genome from normal
cells of an individual, the genes that are driving the cancer can be identified and used as
targets for chemotherapeutic agents. It also will be used to rapidly diagnose and subtype
infectious diseases, particularly those that are difficult to culture. With time, genomics will
change the practice of medicine as more is understood about genetic predisposition to
common diseases such as diabetes and hypertension, enabling physicians to practice health
care rather than disease care.
GENOME SEQUENCING CASE STUDY
A patient presented to Children’s at age 4 for evaluation of failure to thrive, chronic diarrhea
and cryptosporidium infection. She was born at 30 weeks gestational age weighing 560
grams to a then 29-year-old G1, P0. The pregnancy was complicated by oligohydramnios,
IUGR and maternal hypertension, which necessitated early delivery. During her threemonth Neonatal Intensive Care Unit hospitalization, the patient had two episodes of sepsis,
retinopathy of prematurity, TPN cholestasis, feeding difficulties, diarrhea and rickets. She also
had pancytopenia, which resolved.
The patient subsequently had chronic diarrhea and significant failure to thrive with height,
weight and head circumference that were five to six standard deviations below the mean.
She was hospitalized at outside institutions on multiple occasions for infection. Additionally,
she had a small muscular VSD, microcephaly, ear canal atresia on the left and partial
obstruction on the right, significant speech delay and trichorrhexis nodosa (sparse brittle
hair). Clinically, the patient fit the pattern of syndromic diarrhea/tricho-hepato-enteric (SD/
THE) syndrome; however, despite extensive diagnostic evaluations at three institutions, no
definitive diagnosis was identified. Genome sequencing was undertaken, and this identified
pathogenic variants in SKIV2L, a gene recently connected to SD/THE syndrome, a recessive
disorder with an estimated prevalence of 1/1,000,000 births.
Once the diagnosis was established the patient’s providers could avoid further expensive
diagnostic testing, could screen for and manage the medical issues found in patients with
this genetic disorder, and provide guidance concerning prognosis. For her parents, the
diagnosis ended years of searching for a diagnosis, an important outcome for families with a
child who has an undiagnosed genetic disorder.
To learn more about this patient, visit chw.org/genome.
GENOME SEQUENCING AT CHILDREN’S
Children’s has established a Genomic Medicine Clinic, part of the Genetics Center, to care
for children and families where this technology can help. The clinic provides physicians at the
hospital and in the community with a straightforward way to access this testing. The clinic
counsels families about the risks and benefits of testing, arranges insurance preapproval (as
this is an expensive test), provides geneticist input when needed and follows up with families
when testing is complete.
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In most cases, exome sequencing will be pursued as it is less expensive than genome
sequencing. This is because the exome is only 1 percent of the genome and therefore less
sequence data is obtained and evaluated. When needed, however, sequencing of the
entire genome is performed. It is important to note that exome and genome testing are
clinical tests and not research. Currently, a diagnosis is established in about 20 percent of
cases. Both exome testing and genome testing are carried out in the Advanced Genomics
Laboratory, the genomics laboratory of the Department of Pathology and Laboratory
Medicine at Children’s. This laboratory is a joint effort between the Human and Molecular
Genetics Center of the Medical College of Wisconsin and Children’s.
REFER A PATIENT
CALL FOR AN APPOINTMENT
To refer a patient, visit chw.org/refer or
To make an appointment, call Central
call toll-free (800) 266-0366.
Scheduling toll-free at (877) 607-5280.
For more information, visit chw.org/genomics
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Physician Referral and Consultation (800) 266-0366