OMIM Marks A Milestone: 20,000 Entries And Counting

A Hopkins Tradition Keeps Growing Strong

September 2010- Tucked in a corner on the 10th floor of Blalock is the OMIM suite, a cramped warren of offices anchored by a library-in-the-making named for the late Victor McKusick who, for decades, occupied this very space. Lauded as the father of medical genetics, McKusick was a compulsive writer-down of observations; a quintessential chronicler and cataloger of information. 

Among the boxes bursting with genetics books and haphazard piles of scientific journals are 12 editions written by McKusick that comprise the tangible beginnings of Online Mendelian Inheritance in Man (OMIM). 

Victor McKusisk transcribing OMIM notes
during the genetics course in Italy. Photo by
Giovanni Romeo

This comprehensive collection — McKusick described it as a “knowledgebase” of human genes and genetic disorders — had its start nearly half a century ago as fervent jottings in one of the little brown notebooks that he always kept in his lab coat pocket. When he was a boy growing up on a dairy farm in rural Maine, he’d rise at 4 a.m., but now it was to milk genetic insight from his own notes and the biomedical literature. In the predawn quiet, before the demands of research and patients, he’d write, edit and incessantly update the overviews of genes and hereditary traits, or phenotypes, that first became MIM (as the pre-online version was known) and later, OMIM.

Starting in the early 1960s and for the next 30 years, the prolific McKusick was its sole author, writing the text by hand. The first print edition, published in 1966, featured 1,486 entries; most are descriptions of phenotypes. Carol Bocchini, who today serves as editorial director of OMIM, joined McKusick in 1979 as MIM’s first staff editor.

Fast-forward to 2010: Ada Hamosh now directs OMIM’s staff of 11. On April 28, the OMIM team paused from the usual business of reviewing biomedical journals and incorporating the latest genetic findings in what amounts to about 50 new entries and 700 revised entries per month. They hung a homemade sign on which someone had written the numeral two followed by four zeros; the final zero framed a photograph of the smiling face of Victor McKusick. No exclamation point needed. 

Champagne flowed. The countdown had concluded: OMIM officially marked its 20,000th entry.  

In the  1980s and 1990s, McKusick and OMIM were a part of the build-up to the Human Genome Project. “You sort of felt like you were working on the moon-landing mission,” says Joanna Amberger, longtime project manager for OMIM. “It had a going-to-somewhere-big feeling.”  The native Midwesterner — a zoology major in college — didn’t much care for genetics when McKusick hired her in 1986 to work for MIM, she says: “To his credit, his infectious drive, optimism and eagerness to share his knowledge changed my mind.”

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Carol Bocchini, editorial director, Dr. Victor
McKusick, Joanna Amberger, project manager,
and Della Malone (Dr. McKusick's secretary
from 1987 until his death, and now the
secretary for OMIM.)

Although funding for this now government-sponsored entity has come from various sources over the years — the Howard Hughes Medical Institute in the 1980s, and the National Center for Biotechnology Information since the mid 1990s — Johns Hopkins owns the copyright and trademark for OMIM, a freely accessible genetic database that lives on the Web. Every day, 10,000 unique users open 200,000 pages. All over the world, researchers, educators and clinicians refer to it, rely on it. 

A recent survey of users yielded 2,500 responses; notably, nine were from Afghanistan.

“They’ve got bombs falling around them, and they’re answering a survey on OMIM,” Hamosh says not a little incredulously, “which means they’re using OMIM.

“We value all our many users, none more than those clinicians around the world who have no place else to go during emergencies in the middle of the night, who are using OMIM potentially to save lives.”

Among the comments on the various responses:

I often use OMIM to have a quick insight into a gene function or into the clinical presentation of a disease.

I use it daily for diagnostic purposes.

OMIM is the starting point for every project.

Excellent resource — please keep it updated!

OMIM is set to be my homepage and I use it often every day. 

It is the most valuable tool that any clinical geneticist has.

Although other proprietary, for-fee catalogs of genetic disorders exist, none are as comprehensive as OMIM, and none are free, Hamosh says: “To describe it as unique may sound trite, but in the case of OMIM, it’s true.

“You can’t practice medical genetics without it. I’m not saying that because I’m in charge of it.  I’m saying it because I’m a medical geneticist and I frequently make or exclude a diagnosis based on this database.”

Hamosh recalls a for-real for-instance:

“About a year ago, I was called in the middle of the night to see very sick patient in the ICU.  While I was there, someone else asked me to have a look at a full-term newborn just transferred to Hopkins for a next-day surgery to fix a hiatal hernia. I noticed that the baby had a long face, narrow eye openings and a bit of  loose skin. I thought this was so interesting and went into OMIM and typed cutis-laxa (the term for loose skin) and hiatal hernia in the search box on the homepage.  

“One of the things that came up was arterial tortuosity syndrome, which is a clinical way of describing curly or wavy blood vessels. Instead of growing normally, they take too many turns. So I instructed at 1 a.m. that the baby was not to go to the OR the next morning as planned but to imaging instead, because maybe something was going on with her vessels. An MR-angiography confirmed the baby had incredibly tortuous vessels: Her aorta curved out, back and down. A surgeon would not have wanted to discover that after the baby had been opened up.

“Based on a two-minute OMIM search and the findings from the imaging, the baby’s hernia was repaired safely the next day, with no surprises.”

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There’s no question that OMIM serves research and saves lives. But not every entry in OMIM is laden with biomedical jargon describing serious genetic afflictions. The fact that you can roll your tongue (or not) is hereditary; as a result, tongue curling is in OMIM, ID No. 189300. 

OMIM still manages to enlighten and entertain its editorial director and project manager who, collectively, have been in the business of MIM/OMIM for 63 years. Bocchini, who knew much of MIM by heart from having reviewed the entire work every time it went to publication, says to Amberger: “Check out this line (in the tongue curling entry): “ . . . ample time for learning must be allowed in doing family studies of tongue gymnastic ability.” 

Amberger suggests that a lay person perusing OMIM for the first time might also enjoy the entry titled the Jumping Frenchmen of Maine. It has to do with an exaggerated startle reflex, she says, smiling but refusing to divulge more detail. “There are a lot of unusual things in OMIM,” says Amberger. 

Case in point: the Achoo syndrome, a “disorder” characterized by nearly uncontrollable paroxysms of sneezing provoked in reflex action by the sudden exposure of a dark-adapted subject to intensely bright light, usually sunlight. The number of successive sneezes is usually two or three but could be as many as 43. Surprisingly, this entry also includes information on the Berenstain Bears and Aristotle.

Given McKusick’s penchant for chronicling, it’s not surprising that OMIM is rich in historical detail. In the entry titled Porphyria Variegata (MIM ID No. 176200), McKusick noted the suggestion that King George III suffered from porphyria and that the disease could be traced back to Mary Queen of Scots.

“It’s a great place for information junkies,” Amberger says.

Although McKusick created OMIM, was its sole author for three decades and wrote a lion’s share of the entries until his death in 2008, he realized that the pace of genetic discoveries was accelerating and so expanded its staff accordingly.
“He didn’t want OMIM, which he spent so much of his life developing, dependent on his own personal productivity,” Hamosh says. “It lives on because it’s an incredibly useful resource.”

A half-century ago, when McKusick began describing diseases and their inheritance patterns in his notebooks, nothing was known about associated genes. Reflecting advances in science and medicine, MIM rapidly evolved from a catalog of phenotypes into a database of genes and genetic disorders. “The gene behind the phene was always in mind,” McKusick wrote in a scholarly paper commemorating OMIM’s 40th anniversary in 2006. 

Currently, OMIM identifies about 2,500 genes that are mutated in about 4,138 disorders. About 3,000 disorders described in OMIM lack associated genes. However, as next-generation sequencing technology gains traction, those disorders without genes “will fall like that,” Hamosh says, snapping her fingers. 

“This week, we’ve revised the OMIM entry for Kubuki syndrome because the gene mutated in that disorder was just found,” Hamosh says. “I think we’ll see an explosion — it’s starting now — over the next several years. We’ll be identifying the genes for thousands of really rare conditions in the next few years.

“When we understand more about these diseases and the genes implicated, I think that will allow us to get at some fundamental comprehension about the underpinnings of common, complex diseases.

“OMIM will never be finished.”

--by Maryalice Yakutchik