In 1965, when her 10-month-old son, David, started having seizures, Joan Stokes’ excitement at being a first-time mother gave way to terror. “I couldn’t imagine what was wrong,” she said. The pediatrician was equally baffled. David’s condition was not a result of a bacterial infection ? it failed to respond to antibiotics ? and tests for an array of common genetic disorders came back negative.

It was not until Stokes began discussing David’s illness with her mother, her cousins and other relatives that she realised she belonged to a seemingly cursed lineage. “I had a brother that died in infancy who I knew nothing about, and my mother told me, ‘Oh, your brother had the same thing,’” Stokes said .

Other long-hidden stories of baby boys shaking uncontrollably and then dying began to surface and it became clear that the family’s ill-fated heritage stretched back to the 19th century. David, though, clung to life, and a further round of testing revealed that he had low levels of parathyroid hormone.

Suspecting there was a problem with the parathyroid glands, small glands in the neck that ordinarily regulate calcium metabolism, doctors at St. Louis Children’s Hospital gave David high doses of vitamin D to raise his blood calcium to normal levels.

The results were immediate and startling: David’s seizures stopped, and unlike many of his male forebears, he grew and thrived, coasting through childhood without significant developmental delays. A second afflicted son, born two years later, did similarly well on the vitamin D treatment.

Still, the genetic cause of the boys’ disorder, known as X-linked recessive hypoparathyroidism, remained a conundrum. Michael Whyte of Washington University, one of the Stokes children’s doctors, was determined to locate the chromosomal source of the illness.

“There were only two families in the world with this disease, both from eastern Missouri, so we knew the explanation was going to be highly unusual,” he said.

More than 30 years after David’s extraordinarily rare disease was diagnosed, Whyte and his longtime collaborator, Rajesh Thakker of Oxford University, have come a crucial step closer to isolating a biological culprit, finding specific chromosomal abnormalities associated with X-linked hypoparathyroidism.

Their progress in the field offers hope for understanding the thousands of other inherited diseases and disorders that can’t be ascribed to straightforward genetic defects.

But the search was a long one. In the 1980s, Whyte spent days canvassing Missouri in his Toyota Tercel to collect blood samples from 60 members of the two affected families. In 1990, Whyte and Thakker carried out DNA analysis on the samples in hopes of identifying the errant gene responsible for the disorder.

They found no mutations in the PTH gene on Chromosome 11, considered a primary contributor to parathyroid development. But they did notice unusual DNA sequences on the long arm of the X chromosome in many family members. This convinced them that the gene that caused the disorder had to be in a nearby location. “We thought we’d be able to find the gene within about five years or so,” Thakker said. “Little did we know the complexity of what we were dealing with.”

Believing that they were on the verge of a breakthrough, Whyte and Thakker sequenced all the genes in the suspicious stretch of the X chromosome, but found nothing unusual. A different sequencing technique yielded a more promising result, revealing that in each patient, a section of the X chromosome had been deleted and replaced with a section of DNA from Chromosome 2. When the scientists consulted colleagues at the Human Genome Project to find out what genes were in the deleted X chromosome sequence, however, they hit another dead end. The missing section proved to consist of “junk DNA”, stretches that contained no instructions for making protein and had no known function.

Last year, Whyte and Thakker widened the scope of their genetic investigation, sequencing a variety of genes located just outside the missing section of the X chromosome. Previous studies had revealed that one of them, called SOX3, controlled the formation of different types of glandular tissue during development. Whyte suspected that the missing X segment might be close enough to the SOX3 gene to have an effect on its activity. “We began to wonder whether the deletion was somehow influencing SOX3 during early development so that the parathyroid glands didn’t form,” he said.

The labs’ subsequent studies of SOX3 gene activation during mouse embryo development bolstered this theory, showing that SOX3 is active in the right area and at the right time to contribute to the formation of the parathyroid gland. “We think the missing region of the X chromosome ordinarily regulates the expression of SOX3; it acts like an accelerator or a brake,” Thakker said. In X-linked hypoparathyroidism patients, however, “because this regulatory element is out of action, SOX3 is unable to function normally”, he said.