A mutation in the middle of the endothelin receptor type B (EDNRB) gene causes lethal white syndrome when homozygous.

[2][3][4] If pigmented regions are present, they may be any color, and are most common around the muzzle, underside of the barrel, and the hindquarters or tail.

[4] The painful and inevitable death that follows usually prompts veterinarians and owners to euthanize foals suspected of having lethal white syndrome.

[8] Necropsies on LWS foals reveal a pale, underdeveloped colon[2] and intestinal obstruction (impaction).

[9] Genetic conditions which affect more than one physical trait—in the case of lethal white syndrome, both pigment cells and enteric nerve cells—are termed pleiotropic.

The unusual instance of pleiotropy in LWS foals suggested early on that the syndrome was related to an important section of embryonic tissue called the neural crest.

The migration of nerve- and melanocyte-precursors from the top of the embryo to their eventual destinations is carefully controlled by regulatory genes.

[11] The resulting EDNRB protein is unable to fulfill its role in the development of the embryo, limiting the migration of the melanocyte and enteric neuron precursors.

[5][7][9][13] Frame is characterized by jagged, sharply defined, horizontally oriented white patches that run along the horse's neck, shoulder, flank, and hindquarters.

[9] One study found from a group of visually inspected registered Paints, 18% of breeding stock solids and 35% of bald-faced horses were actually frames.

[9] Any combination, or all, of these white-spotting genes can act together to produce horses with so much white that the presence of frame cannot be determined without a DNA test.

[24] Likewise, official classification of a horse as an unspotted solid is based not on genetic testing, but on a visual description.

Horses carrying genetics for frame and other white-spotting patterns may be so minimally marked as to lack the registry's minimum requirements for white.

[25] This helps to account for allegedly solid horses producing spotted offspring, called cropouts.

Producing a foal with LWS is now completely avoidable, because most major animal genetics labs now offer the DNA test for it.

[27][28][29] Lethal white syndrome is described as recessive because heterozygotes (written Oo or N/O) are not affected by intestinal agangliosis.

[31] The majority of horses with the Ile118Lys mutation do exhibit the recognizable frame pattern, but a small percentage are too modestly marked to be classified as "spotted" by breed registries.

Before reliable information and the DNA test were available to breeders, perfectly healthy, white-coated, blue-eyed foals were sometimes euthanized for fear they were lethal whites,[14] an outcome which can be avoided today with testing and a better understanding of coat color genetics or even waiting 12 hours or so for the foal to develop clinical signs.

From very early in research into its genetics,[4] LWS has been compared to Hirschsprung's disease in humans, which is also caused by mutations on the EDNRB gene.

Various polymorphisms on this gene result in intestinal agangliosis, in some cases attended by unusual pigmentation of the skin and eyes, and deafness.

[5] The terms "piebald-lethal" and "spotting lethal" apply to similar conditions in mice and rats, respectively, both caused by mutations on the EDNRB gene.

[36][37] Only lethal in the homozygous state, the mutations are associated with white-spotted coats, deafness, and megacolon caused by intestinal agangliosis.