Agrawal Laboratory

Researchers at the University of Miami Miller School of Medicine, Boston Children’s Hospital and the Manton Center for Orphan Disease Research have shown that mutations in the HBS1L gene disrupt eye function and cause retinal dystrophy.

The study was published in the journal Disease Models and Mechanisms.

“As far as we know, the mutations in this specific gene affect only one person in the world,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the Miller School Department of Pediatrics and Jackson Health System. 

A large, international research collaboration has shown that whole genome sequencing (WGS) can better determine the genetic causes of rare diseases than whole exome sequencing (WES).

WES only reads protein-producing genes, around 2% of the genome, according to a study published in the New England Journal of Medicine.

“For many years, people have been asking whether genome or exome is the better approach,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the University of Miami Miller School of Medicine Department of Pediatrics and Jackson Health System and co-author on the paper. 

Caused by mutations in the CFTR gene, cystic fibrosis (CF) affects multiple organs, particularly the lungs. While the condition has been heavily studied, a number of mysteries remain, including why patients with the most common DeltaF508 mutation in the CFTR gene can have radically different outcomes.

Researchers at the University of Miami Miller School of Medicine and other schools have shown that variants in a related gene, SLC26A9, can worsen CF. 

Riley Kogen never got the chance to realize her legacy of becoming a University of Miami Hurricane and follow in the footsteps of her mother, Ali Nathan, B.Sc. ’03, and grandfather, Bob Denholtz, B.B.A. ’71. Riley passed away a decade ago, at only five years of age, from panhypopituitarism, a rare condition that affects the production of hormones in the pituitary gland.

Hoping to prevent other families from experiencing similar heartbreak, her family created Riley’s Dance Fund, named in honor of the blue-eyed little girl who loved to twirl.

​

Their philanthropy supports the groundbreaking work of Pankaj Agrawal, M.D., chief of the Division of Neonatology. 

In a study published in the Journal of Cachexia, Sarcopenia and Muscle (JCSM), researchers at the University of Miami Miller School of Medicine, Boston Children’s Hospital, Brigham & Women’s Hospital and Harvard Medical School have shown how mutations in the SPEG protein can derail muscle function and cause disease.

Using a complex, multi-omic approach, the team showed how SPEG interacts with multiple skeletal and heart muscle proteins and regulates them.

“We have been studying SPEG for more than 10 years,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the University of Miami Miller School of Medicine.

Genome sequencing has proven its value many times over, particularly in the neonatal intensive care unit (NICU). Rapid sequencing can identify underlying genetic conditions, leading to precise diagnoses and effective treatments for newborns with very serious medical conditions.

But genomics is not yet a plug-and-play solution. Hospitals need infrastructure and expertise to make it work. Major academic teaching hospitals have the resources to get it done. Small community hospitals generally do not.

​

In an effort to level the playing field, Pankaj Agrawal, M.D., chief of the Division of Neonatology in the University of Miami Miller School’s Department of Pediatrics, and colleagues at Boston Children’s Hospital and elsewhere created the Virtual Genome Center for Infant Health (VIGOR).

Genome sequencing can identify genetic variants that may cause disease, but the answers aren’t always clear. Variants of uncertain significance (VUS) can cloud the picture, leaving patients and families in a diagnostic no-man’s land.

Now, in a study published in the American Journal of Medical Genetics, researchers at the University of Miami Miller School of Medicine have shown that carefully reevaluating VUS can generate concrete diagnoses. These approaches could help physicians and researchers solve numerous medical mysteries, potentially matching patients with effective treatments and clinical trials.​

Genomic sequencing has the potential to diagnose rare genetic diseases in newborns. But these technologies have yet to be widely adopted, limiting access to care.

In a review published in the European Journal of Human Genetics, a Nature journal, neonatologists at the University of Miami Miller School of Medicine, Holtz Children’s Hospital of Jackson Health System, Harvard Medical School and Boston Children’s Hospital examined the current neonatal sequencing landscape to see how it can be improved.​

Ryan and Rachel Belanger have a bittersweet relationship with Pankaj Agrawal, M.D., chief of the Division of Neonatology in the Miller School’s Department of Pediatrics and Jackson Health System. In 2017, the renowned neonatologist identified the rare metabolic disorder that claimed the life of their newborn daughter, Bella. Years later, that same knowledge ensured that their two sons wouldn’t suffer the same fate.

​

“When we met Dr. Agrawal, we knew we were in the best hands,” Rachel said. “The way he made us feel and the way he treated us, we knew that he wouldn’t stop searching for answers.”

About a year and a half ago, Robert Rothstein, MD, FAAP encountered a baby with a pattern of facial features and clinical findings that suggested a genetic syndrome. The available tests couldn’t pinpoint a diagnosis, and the family wanted a more definitive answer. So Rothstein and his colleagues transferred the newborn from Baystate Medical Center (Springfield, Mass.) to Boston Children’s Hospital — 90 miles away — for a more in-depth genetic workup.

By the time the parents met with the Boston Children’s team to discuss their baby’s genetic diagnosis, they were anxious and mistrustful. The neonatal intensive care unit (NICU) team in Boston suggested patching Rothstein into the family conferences and decision-making.

Suheil Day was born early, at 37 weeks. Aside from a slight head lag and mild muscle weakness, nothing seemed terribly amiss. But as the months progressed, he began having seizures.
 

“At the age of 4 to 5 months, he started waking up screaming and crying excessively, his eyes rolling up into his head,” says his mother, Nadeen.
 

Suheil’s physicians in Israel diagnosed him with West syndrome, an infantile spasm disorder, and treated him with adrenocorticotropic hormone. His seizures abated, but only for six months. After 15 other medications were tried without success, the Israeli hospital arranged for whole-exome sequencing to look for a genetic cause. The results showed variants in four genes. Two genes were ruled out after more testing; the other two were unknown.

A growing number of children with suspected genetic disorders are having their complete exomes sequenced, since it’s now often faster and cheaper to sequence all the protein-coding genes at once rather than test limited groups of genes. But even after whole-exome sequencing, 70 to 75 percent of children come away without a genetic explanation for their illness.

​

More and more clinicians are sending these families to Pankaj Agrawal MD, MMSc, a neonatologist at Boston Children’s Hospital and medical director of the Gene Discovery Core at Boston Children’s Manton Center for Orphan Disease Research. The Core can then do a deeper dive. Its services are available to any patient or family looking for a second opinion, including families whose child is deceased.

Two rare groups of CF patients may reveal new approaches to treatment. They are outliers: patients whose disease progresses much more rapidly or slowly than is typical despite the same mutation.

​

A Boston Children's team scoured the genomes of five outliers in search of genes that might modify the effects of the CF mutation and this explain these differences. They found several and are creating patient-specific stem cell models to further study the interactions of the modifier of CF genes. The team --physician scientist Ruobing Wang, stem cell scientists Carla Kim and George Q. Daley, and geneticist Pankaj Agrawal -- hopes that insights from outliers will lead to new treatments for CF patients who do not benefit from today's drugs.  

When the 1-year-old boy arrived from overseas, he was relying on total parenteral nutrition — a way of bypassing the digestive system to provide nutrients and calories completely intravenously — to survive. From the time of his birth, he had experienced unexplainable diarrhea. Answers were desperately needed.

​

Sequencing his genes in search of clues, neonatologists and collaborators at the Manton Center for Orphan Disease Research at Boston Children’s Hospital identified a new gene mutation responsible for chronic congenital diarrhea — even finding a similar mutation in two other children as well.

The answer may be hidden in their genes.

Cystic fibrosis is an inherited disorder caused by genetic mutations that disrupt the normal movement of chloride in and out of cells. Among other health problems, cystic fibrosis compromises the lungs’ ability to fight infection and breathe efficiently, making it the most lethal genetic disease in the Caucasian population. Patients have an average lifespan of just 30 to 40 years.

Despite this narrow average lifespan, there is a big range in how severely cystic fibrosis (CF) affects the lungs and other organs depending on an individual’s specific genetic variation, and even in how long patients sharing the same, most common genetic mutation are able to survive with CF.

The first complete autopsy findings for a patient with AIFM1-associated disease are described in a paper from Morton et al. A novel variant in AIFM1 was identified in an infant who presented with severe metabolic acidosis, myopathy, and neuropathy. Shown here is a Gomori trichrome image of quadriceps muscle biopsy, 100×, showing features of mitochondrial myopathy including coarse stippling and scattered fibers with subsarcolemmal aggregates corresponding to mitochondria. (For details, see Morton et al., this issue; doi: 10.1101/mcs.a001560.)

Examining the tragedies of several families who each lost multiple children, two teams of researchers reveal a previously unappreciated role for a mitochondrial enzyme.

Head magnetic resonance imaging (MRI) findings in a female patient with severe mitochondrial disease presenting with developmental delay, hypotonia, lactic academia, and brain atrophy. Whole-exome sequencing identified two variants in the PMPCA gene, which encodes for α-mitochondrial processing peptidase (α-ΜPP), a protein likely involved in the processing of mitochondrial proteins. Shown here is the head MRI image of the patient at 6 months of age, which reveals cerebellar atrophy with enlarged interfolial spaces, whereas marked cerebral and cerebellar atrophy with enlarged ventricles were noted at 3 and 6 years. (For details, please see Joshi et al., this issue; doi: 10.1101/mcs.a000786.)

The coming year will see increased focus on genome sequencing of sick babies as an aid to their medical diagnosis and management. In 2013, the NIH funded four grantees across the U.S. to explore the use of genome sequencing in newborn health care for a period of five years, including a joint project from Boston Children’s and Brigham and Women’s Hospital. In the future, genomic sequencing may expand to all newborns as sequencing technologies get more affordable and sequence data get more interpretable. This may not only help improve care for those babies but also guide their families in making future decisions. —Pankaj Agrawal, MD, MMSC, Newborn Medicine Research Center, Boston Children’s Hospital

Sequencing a patient’s genome to figure out the exact source of his or her disease isn’t standard operating procedure — yet. But falling sequencing costs and a growing number of successes are starting to bring this approach into the mainstream, helping patients and families while advancing a broader understanding of their diseases.