The KANSL1 gene provides the blueprint for a protein that is active in tissues and organs throughout the body from before birth into adulthood. This gene is a fundamental component of the body’s machinery for regulating other genes, ensuring they are turned on or off at the correct times to orchestrate proper growth and function.
The Biological Role of the KANSL1 Gene
The KANSL1 gene’s primary function is to act as a manager of genetic activity. It produces a protein that is a member of a group called the KAT8 regulatory NSL complex. This complex functions as a histone acetyltransferase (HAT), which is involved in modifying chromatin—the tightly packaged structure of DNA and proteins inside our cells.
Histone acetylation, the process the NSL complex is involved in, helps to “unpack” segments of DNA, making the genetic instructions within accessible for the cell to read. The KANSL1 protein itself is non-catalytic but is a necessary part of the machinery that performs the chemical reaction. By helping to control which genes are available, the KANSL1 protein plays a significant part in the normal development and function of many systems in the body, including the brain.
This regulatory role extends to processes beyond development, as the KANSL1 protein is also involved in ensuring proper cell division, known as mitosis. It contributes to the stability of microtubules, which are structures that form the cellular “skeleton” and are essential for separating chromosomes correctly when cells divide.
KANSL1-Related Genetic Conditions
When the KANSL1 gene is altered, its ability to regulate other genes is disrupted, leading to a specific set of developmental differences. The primary condition caused by changes to this gene is Koolen-de Vries Syndrome (KdVS). This syndrome occurs when an individual has only one functioning copy of the KANSL1 gene instead of the usual two, a loss of function referred to as haploinsufficiency.
The genetic change responsible for KdVS can happen in one of two ways. Most commonly, it results from a microdeletion on chromosome 17, in a region labeled 17q21.31, which removes a segment of DNA that includes the entire KANSL1 gene. Less frequently, the syndrome is caused by a pathogenic variant, or mutation, within the KANSL1 gene itself.
These genetic changes are almost always de novo, a term used to describe a new mutation or deletion that appears for the first time in a family. It occurs spontaneously during the formation of reproductive cells or in early embryonic development. This means that the condition is not inherited from a parent.
Common Characteristics and Symptoms
Individuals with Koolen-de Vries Syndrome share a recognizable pattern of developmental, physical, and behavioral traits, though the specific features can vary. Developmentally, a near-universal characteristic is psychomotor delay from an early age, affecting skills like sitting, crawling, and walking. Most individuals function in the mild-to-moderate range of intellectual disability, and speech and language delays are particularly pronounced.
A prominent feature in infancy and early childhood is hypotonia, or low muscle tone, which can make a child seem “floppy” and can contribute to feeding difficulties. Seizures or epilepsy affect approximately one-third to one-half of individuals with KdVS and may require management with medication.
People with the syndrome often share distinctive facial characteristics and associated health conditions. These can include:
- A broad forehead, droopy eyelids (ptosis), and a pear-shaped or bulbous nose
- Congenital heart defects, such as atrial or ventricular septal defects
- Kidney and urinary tract abnormalities
- Skeletal issues like flexible joints, flat feet, or curvature of the spine (scoliosis)
Despite the developmental and medical challenges, a notable aspect of KdVS is a distinct behavioral profile. Many individuals are described as being exceptionally friendly, amiable, and cooperative, although some may also experience behavioral issues like hyperactivity.
Diagnosis and Genetic Testing
While a combination of symptoms such as developmental delay and hypotonia may lead a doctor to suspect Koolen-de Vries Syndrome, a definitive diagnosis requires genetic testing. Standard chromosome analysis cannot detect the small deletion that causes the syndrome, so specialized molecular tests are necessary.
The most common diagnostic tool used is a chromosomal microarray (CMA). This test analyzes chromosomes on a microscopic level and can identify the small, missing piece of genetic material on chromosome 17q21.31 that is characteristic of the syndrome.
If a CMA test comes back normal but clinical suspicion for KdVS remains high, the next step is often gene sequencing. This type of testing reads the exact sequence of the DNA letters that make up the KANSL1 gene. It is used to find a single pathogenic variant within the gene that would not be visible on a microarray.
Management and Support Strategies
There is currently no cure for the underlying genetic cause of Koolen-de Vries Syndrome. Management focuses on supporting the individual, treating symptoms, and maximizing their developmental potential through a coordinated, multidisciplinary approach.
Early intervention services are used to address developmental needs. Physical therapy is used to address hypotonia and improve gross motor skills, while occupational therapy helps with fine motor coordination and daily living activities. Given the significant impact on communication, speech therapy is important for developing language and addressing potential feeding issues in infancy.
Proactive medical surveillance is another component of care. Regular appointments with specialists are needed to monitor for and manage associated health conditions. This may include visits to a cardiologist to check the heart, a nephrologist for kidney function, and a neurologist to manage epilepsy. Regular eye exams are also recommended, as farsightedness is common.