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June 30, 2017
Genetics, Evolutionary Biology Help Identify Rare Mendelian Disorders

If Charles Darwin had read the findings of Gregor Mendel, he might have saved himself a lot of grief. While Mendel was holed up in a monastery discovering hereditary traits by experimenting on pea plants, Darwin was struggling to prove his theories of natural selection and descent-with-modification.

“Darwin’s big problem was that, with descent-with-modification, there was no theory of genetics, no knowledge of genetics, so he had no way of explaining how variations that were favorable were transmitted from one generation to the next,” said geneticist Dr. David Valle at a recent Clinical Center Grand Rounds in Lipsett Amphitheater, Bldg. 10.

Dr. David Valle
Dr. David Valle

A century after Darwin, in the 1960s when Valle was a medical student, he never heard evolution mentioned. “Evolution was [thought to be] paleontology and fossils,” said Valle, director of the Institute of Genetic Medicine and professor of pediatrics, ophthalmology, molecular biology and genetics at Johns Hopkins University. “But nothing could be more removed from medicine and the biology of human beings.”

Biology and medicine are rooted in evolution, said Valle at this Great Teachers edition of rounds. “And genetics is emerging as the basic science of all medicine,” he said. “Our genomes have to stand us in good stead throughout our lifetime.”

We’ve come a long way from Mendel’s cross-breeding of pea plants to advances in recent decades that led to sequencing whole genomes. With more than 60 million different SNPs (single nucleotide polymorphisms, or, genetic variations) in humans and more than 3 million between individuals, it’s a wonder people get sick. But when genetic variations pull us from the median, combined with environmental stresses that bump us out of homeostasis, we’re susceptible to illness.

“Getting sick is really a consequence of variation, natural selection and, [therefore], evolutionary biology,” said Valle.

Human genome sequencing has given us a parts list, namely all 20,000 protein-coding genes. The challenge is figuring out how these proteins interact with each other in biological systems and how these systems function in tissues and organs. A genetic strategy to meet this challenge is to identify patients with mutations that result in malfunction of one of these systems and thereby tell us something about the role of the system in health and disease, said Valle.

Over the years, his lab has discovered the genetic causes of more than 20 diseases and continues to use genetic tools to find and understand rare Mendelian disorders. Most patients with these disorders have egregious defects, he said, and present early, often in childhood. They also are more likely to inherit a rare variant from both sides of the family and have multiple siblings or generations with the same disease.

In one curious case, a seemingly healthy 34-year-old male contracted an infection but was unresponsive to treatment. He developed confusion and arrived at JHU with cerebral edema. After interviewing the family, Valle learned that the patient’s brother had drowned as a teenager. Upon further probing, Valle discovered that the teen showed signs of confusion the day he died and an autopsy revealed cerebral edema.

The patient survived what turned out to be ornithine transcarbamylase (OTC) deficiency. His parents kept his late brother’s baby tooth and DNA testing confirmed the same variant; his mother and aunt also tested positive. The late brother had an episode of hyperammonemia secondary to OTC deficiency as a child; the surviving brother didn’t show signs until adulthood.

Valle presents at a Great Teachers edition of CC Grand Rounds.
Valle presents at a Great Teachers edition of CC Grand Rounds.


“The only thing that got him was he had this severe environmental stress—which was infection and fever—perhaps augmented by a dose of steroids, which puts excessive demands on the urea cycle,” said Valle. “It wasn’t until his system was really stressed that this homeostatic vulnerability came to light.”

Researchers increasingly are uncovering new gene variants for all kinds of Mendelian disorders thanks to rapid genome sequencing. While there are different advantages to single-gene and panel (20-30 genes) sequencing, whole exome sequencing has been especially useful in diagnosing patients with phenotypes caused by variants in genes not previously known to be responsible for disease. These efforts have not only identified hundreds of novel disease genes but also have explained many surprises. One example is patients who have two rare Mendelian disorders. These “multi-Mendels” have been difficult to diagnose because their blended phenotypes are hard to recognize, said Valle. A precise diagnosis from whole exome sequencing can be invaluable, he said, as it ends the diagnostic uncertainty, suggests specific management and informs the family of recurrence risk.

NHGRI established four Centers for Mendelian Genomics to recruit families from around the world to sequence whole exomes. The Baylor-Hopkins Center for Mendelian Genomics, where Valle is a principal investigator, so far has discovered 913 novel disease genes in its first 5 years.

Valle’s group also developed two online databases to promote resource sharing. PhenoDB ( allows any provider to submit a case and features an analysis tool. GeneMatcher ( connects clinicians worldwide. As of March 2017, more than 6,000 genes were submitted by nearly 3,000 people. Although two-thirds of the genes remain unmatched, so far more than 15,000 matches have been found for some 2,000 genes.

The late biophysicist Max Delbrück once said, “Any living cell carries with it the experience of a billion years of experimentation by its ancestors.” As we continue to evolve and learn more about our genes and disease-causing variants, investigators can identify new drug targets and develop better diagnostics and therapies.

“If we look carefully and across large populations,” said Valle,” I predict we will find Mendelian phenotypes for certain variants for nearly all genes in our genome.”

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