You’re used to having blood tests when you go to the hospital, but soon patients at Hadassah Medical Organization will be asked to give DNA samples, too. In an institution that has already identified more than 100 new disease-associated genes, patients will contribute to and be helped by the gene pool, called Hadassome, Hadassah’s exome database. With 5,000 records, it’s the largest variants’ databases in Israel.

Head of Bioinformatics Dr. Hagar Mor-Shaked, hurries each morning from her home in Ein Kerem village to her computer screen in the Genomic Sequencing Lab at Hadassah’s Ein Kerem campus to solve genetic mysteries that unlock the causes of diseases. Most of her work involves the art of exome sequencing: reviewing the patient’s approximately 180,000 exons containing the most important DNA.

Her team predominantly researches so-called monogenic diseases which are controlled by a single gene, such as Cystic Fibrosis, Tay-Sachs disease and Smith-Lemli-Opitz syndrome. However, the Hadassah team also identifies rare diseases that have never been named.

In October 2019, Hadassah marked the publication of its 100th paper on new disease-associated genes. The geneticists are about to announce a further 10 genes in the coming months.

Contributing to the success is the Israeli gene pool’s unique composition. Many cousins marry each other, and extended families are large and often have multiple presentations of syndromes. The combination of traditional families and the most advanced medicine makes Hadassah ideally positioned to solve mysteries.

“A child arrives at a clinic and the doctor doesn’t know what the problem is and doesn’t have a name for the disease,” says Dr. Mor-Shaked. They send an exome sequencing and we try to find out what’s gone wrong.”

A typical case is a local family in which cousins have married. Their oldest son, 22, is healthy. The next five children died within their first year of life. Before the last child died, DNA was preserved. In October 2019, the parents came to Hadassah with their sad history and the news that the mother was pregnant. Hadassah geneticists were able to identify a homozygous mutation in the BRAT1gene. They then tested the embryo and found the child wouldn’t have the disease, but only would be a carrier. Encouraged that they will have a second healthy child, they are going ahead with the pregnancy. The disease that runs through the family is known as lethal neonatal rigidity and multifocal seizure syndrome.

Dr. Mor-Shaked sees a deep psychological value in being able to determine a disease.

“It’s not enough to say a child is going to be blind, deaf and autistic,” she says. “Parents need to know why. Once the disease is discovered and named, some families have created charitable organizations for other families dealing with the same disease.”

Using Hadassome, geneticists can compare a current case with the exomes of people of a similar ethnic background. If the case under investigation does not match existing records then doctors know they are dealing with a new variant. That variant is added to the database.

The world’s largest publicly-available exome database, is gnomAD held by the Broad Institute in the United States. It contains exomes of many Ashkenazi Jews, but lacks the exomes from people of Middle-Eastern origin that Hadassah has.

Hospitals around the world are already contacting Hadassah because of the database.

“We’re frequently called to give a second opinion,” Dr. Mor-Shaked says. “Because of Hadassome and our experience we’re in a better place than most to say what might be a disease-causing variant, a new disease-causing gene, and which is a new disease.”

Exomes don’t change. That means as new diseases are discovered, Hadassah can now re-contact old patients and offer them updated solutions.

In the last few month, Hadassah has purchased a NovaSeq6000, the most advanced high-throughput sequencer, and has shifted to perform the DNA sequencing in-house. This has caused a sharp increase in exome analysis.

As the Hadassome cohort grows, Hadassah labs will begin examining more complex diseases, reactions to drugs and why some patients can undergo general anesthetic but others cannot. This is all part of Hadassah’s broader move toward personalized medicine. 

“Most of the time I’m behind the scenes,” says Mor-Shaked, a mother of two small children. “Emotionally, it’s a bit easier for me because I don’t take the sad faces home with me, although learning about that family that had to bury five babies makes me even more determines to locate the cause. There’s also the fear of making a mistake. The responsibility is immense. It’s a puzzle, but when you find the solutions you can change lives for the better.”