Probing the genetic substructure of the population of East Harlem has identified an orthopedic syndrome that is rare in the general population, but appears to be clustered among people of Puerto Rican ancestry. Properly diagnosing the condition may save children from hip surgery that can actually worsen symptoms.
Steel syndrome causes joint pain, hip dislocation, pinching of the spinal cord in the neck (cervical stenosis), short stature, and characteristic facial features. Gillian Belbin, MS, a graduate student working with Eimear Kenny, PhD, an assistant professor in Genetics and Genomic Sciences at the Institute of Personalized Medicine at the Icahn School of Medicine at Mount Sinai and their colleagues discovered the condition in the community. But as often happens in genetic research, they weren’t looking for it.
“We are using hidden patterns of relatedness in genetic data of New York City populations to infer demography and ancestry,” Ms. Belbin told me
at the American Society of Human Genetics
annual conference in Baltimore on October 9. Once the team had analyzed enough data to be able to distinguish people of Puerto Rican ancestry genetically, the researchers noticed several individuals who had a peculiar collection of musculoskeletal anomalies.
The researchers genotyped 600,000 SNPs – variations in the DNA base at specific sites in the genome – in 11,000 of the 32,000 DNA samples in the BioMe biobank
that Mt. Sinai began in 2006. Specifically, they looked for stretches of shared SNP patterns, which indicate “identity-by-descent” -- inheritance from recent common relatives, like people who have the same great-great-grandmother. “We can pull out different demographic subgroups within our population that self-identify as Ashkenazi Jewish or Puerto Rican, for example, or populations of the African diaspora,” said Ms. Belbin. When the researchers add information about ancestors and countries of origin, and electronic health records, patterns emerge.
SNP genotyping can tease out shared ancestry and diseases that are more prevalent in certain population groups - entire genome sequences aren’t necessary. It’s like flipping through a book and seeing “Dorothy,” “tin woodman,” “scarecrow,” and “Cowardly lion” and realizing it is The Wizard of Oz
, and not the Manhattan phone book, without reading the whole book.
The Puerto Rican genetic signature is so strong that the researchers use it to tell people who know only that they’re Hispanic/Latino that their ancestors came from the island. The approach “catches waves of diaspora that are like islands in the city reflecting patterned and structured migration routes,” said Dr. Kenny, who as a population geneticist is unusual among the clinicians and epidemiologists at Mt. Sinai. “This helps us find people who have distant relatedness in these communities. They may or may not have been born in Puerto Rico or have relatives who were, but are of Puerto Rican descent,” she added.
The key to Steel syndrome was simple and obvious, in retrospect: height
. In the Puerto Rican population of East Harlem, short stature tended to occur with joint pain, joint replacements at young ages, and emergency cervical stenosis. The unusual collection of symptoms clearly ran in families, passed from carrier parents in an apparent autosomal recessive mode of inheritance. “We could see quite clearly without knowing what it was that it was an orthopedic syndrome,” Dr. Kenny said.
Then last March, the Mt. Sinai researchers read a report from investigators
at the Baylor College of Medicine. They had used whole exome sequencing to identify the mutations behind several disorders of cartilage and bone (osteochondrodysplasias), and found a mutation in a collagen gene (COL27A1
) that causes something called Steel syndrome.
Orthopedist Howard H. Steel was the first to describe the condition that would take his name, in a report from 1993
about 23 children from Puerto Rico. In addition to the symptoms noted above, he documented reduced joint mobility, soft bone tips, dislocated elbows and hips, fused finger and toe bones, scoliosis, high arches, and the short stature that tipped off the Mt. Sinai team. Most importantly, Dr. Steel advised against
hip surgery, because the nature of the problem is different than common indications.
It wasn’t until 2010
when Steel syndrome was heard from again. John M. Flynn, MD, and colleagues confirmed Dr. Steel’s original admonition that children with the syndrome fare better without
hip replacement. Surgery to restore the alignment of the hip bones, called hip reduction, isn’t the same for people with Steel syndrome as it is for hip dislocation from injury, such as from a car accident or skiing into a tree.
The 2010 paper fleshed out the phenotype even further: a large head with a long, oval face, broad nose, small low ears rotated slightly backward, and a prominent forehead. Such details of “dysmorphology” are a hallmark of medical genetics. To a pediatrician encountering a patient of Puerto Rican ancestry who’s short and has joint problems, the telltale facial characteristics can provide a crucial clinical clue.
Both the 1993 and 2010 studies didn’t find consanguinity (relatives having children with relatives). Therefore, the higher prevalence of Steel syndrome in the community of people from Puerto Rico is likely due to a founder effect. An original settler or settlers brought in a recessive mutation that, over time, ended up in two copies in some individuals whose parents were very distantly related but didn’t know it.
When the paper from Baylor came out in March 2015 identifying the mutation behind Steel syndrome, Dr. Kenny and Ms. Belbin rushed back to their data to search for the “signal.” (The mutation changes a glycine to an arginine in the COL27A1
collagen gene.) And they found it: 6 cases among the 8,000 or so people of Puerto Rican ancestry living in the area. The disease appears to otherwise be so rare that I couldn’t even find prevalence statistics, just the cases in the handful of published reports. Although a full medical genetics work-up and clinical diagnosis must confirm what the genotype suggests, 6 out of 8,000 is clearly not ultra-rare.
Because Dr. Kenny hadn’t expected to discover a possible cluster of a rare genetic disease in her study of the East Harlem subpopulation, and the work is preliminary, the project isn’t set up to re-contact biobank participants who may have it. However, plans are now underway to educate clinicians to recognize the syndrome, and Mt. Sinai is adding Steel syndrome to its list
“This is a gene variant that is specific for the 8000 Puerto Ricans in the population. If you’re looking at Hispanics as a whole you may not find it, because it is much less frequent in that population than if you understand the finer scale structure of the population. For Steel syndrome if we look only at Puerto Ricans, we have much better power to make the discovery. But we didn’t know going in that it was there,” Dr. Kenny concluded.
The finding of a rare inherited condition in people united by ancestry will be echoed as the Precision Medicine Initiative gets underway and embraces biobank projects already up and running. Concluded Dr. Kenny, “In genomics research, as we are sequencing millions of people, the more we appreciate that rarer and rarer gene variants hold the burden of disease risk. These variants are likely to be geographically and regionally specific and restricted.”
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