Years published: 2023
NORD gratefully acknowledges Amanda J. Grieco, PhD and Natacha Esber, MD, Director, Research and Scientific Committee, KAT6 Foundation, for assistance in the preparation of this report
KAT6B-related disorders are extremely rare genetic neurodevelopmental disorders caused by changes (pathogenic variants or mutations) in the KAT6B gene. Neurodevelopmental disorders impair or alter the growth and development of the brain and the central nervous system. Variants in the KAT6B gene can lead to a broad spectrum of signs and symptoms, some of which can be grouped into genitopatellar syndrome (GPS) or a type of Ohdo syndrome called Say-Barber-Biesecker-Young-Simpson (SBBYS) but features very frequently overlap. Commonly, these include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), feeding difficulties, diminished muscle tone (hypotonia), abnormalities affecting the heart, hips or knees and growth problems. Less common features include hearing impairment, seizures and autism-like behaviors, and abnormalities of the thyroid gland, skull, genitals, kidneys and teeth. In most instances, variants in the KAT6B gene occur spontaneously and there is no family history of the disorder (de novo variants). Treatment is based on the specific symptoms present in each individual.
Variants in the KAT6B gene can lead to a broad spectrum of signs and symptoms. On either side of the spectrum are some clinical features that are associated more often with either genitopatellar syndrome (GPS) or a type of Ohdo syndrome called Say-Barber-Biesecker-Young-Simpson (SBBYS). But individuals affected by KAT6B-related disorders frequently have intermediate clinical features that are a mixture or overlap between these two syndromes. Some individuals have clinical features that do not overlap with either syndrome at all.
The potential symptoms associated with a variation in the KAT6B gene are numerous and highly variable and can depend on the specific type of variant (e.g., type of mutation, or location in the gene). This is called genotype-phenotype correlation. It is important to note that every child is unique and how the disorder affects one child can be very different from how it affects another.
Neurologic features are present in most individuals affected by KAT6B-related disorders. A child’s progression through predictable developmental phases, like sitting up and crawling, may be slowed, stopped or reversed (developmental delays). Global developmental delays can affect both motor functions, like walking, and intellectual development ranging from mild to severe. Speech delays and language disorders are frequent, though some individuals can communicate through vocalization or manipulating objects. Some brain anomalies are more common in individuals affected by GPS including an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum) that can contribute to developmental delays and can sometimes cause seizures. Less frequently, an unusual amount of cerebrospinal fluid can increase pressure on the brain and cause damage or seizures. Individuals affected by SBBYS are more likely to have an underdeveloped or damaged optic nerve, and impairments in the region of the brain that processes visual information (cortical visual impairment). These can lead to visual deficiencies in one eye (lazy eye) or nearsightedness.
Most individuals affected by KAT6B-related disorders have feeding difficulties and gastrointestinal features. Feeding challenges can include difficulty coordinating motor functions and swallowing (dysphagia) which can lead to choking or breathing food, liquid or other foreign material into the lungs (aspiration). Most individuals, especially infants, can have a backflow of the contents of the stomach into the esophagus (gastroesophageal reflux). In some individuals, improper development of the intestines may cause them to settle in the wrong parts of the abdomen, which can cause them to become blocked or twisted (small bowel malrotation) and lead to frequent vomiting or constipation. Additionally, individuals with GPS are more likely to have anal abnormalities, including no anus (anal atresia), a narrowing of the anal canal (anal stenosis), or mispositioning of the anus closer to the front of the body. These conditions can lead to serious health complications from a failure to pass stool.
Some individuals affected by KAT6B-related disorders have low muscle tone (hypotonia) and muscle abnormalities. For infants especially this can further complicate feeding and breathing, but often difficulties resolve in infancy. In GPS, infants are more likely to have an abnormality where tissue located above the voice box flops back over the upper-airway (laryngomalacia) and obstructs breathing. Beyond infancy, hypotonia of extremities and the trunk may continue. Nearly all individuals affected with GPS have permanently short and tight muscles (contractures), primarily in the knees and hip, that significantly restrict flexibility and movement. In SBBYS, contractures only occasionally occur.
Skeletal and growth abnormalities can also occur. Affected infants may have a condition in which head circumference is smaller than would otherwise be expected based on age and gender (microcephaly). Rarely, flexible sutures in spaces typically found between bones of a baby’s skull turn into bone and join prematurely (craniosynostosis). This can cause changes in skull growth patterns that often result in a misshapen head. In children, additional growth abnormalities can include varying degrees of poor weight gain, diminished physical growth and below average height. More common in individuals affected by GPS are underdeveloped (hypoplastic), dislocated or absent kneecap (patella), clubfoot, and bone abnormalities of the spine, ribs and pelvis. Individuals affected by SBBYS are more likely to have toe and finger abnormalities, and most individuals will have long thumbs and great toes.
Roughly half of affected individuals have heart defects that are present from birth (congenital heart defects). These can include atrial and ventricular septal defects. Septal defects are when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles, or in the membrane that separates the two upper chambers of the heart, called the atria. Additionally, normal openings in the fetal heart may fail to close at birth (patent ductus arteriosus and patent foramen ovale). Incomplete closure of these holes can allow varying amounts of blood to bypass the lungs where they would normally pick up oxygen. The size of these ‘holes will determine whether any symptoms are present, and how severe these symptoms may be.
Distinct facial features associated with KAT6B-related disorders commonly include low-set ears, prominent cheeks, a flat and broad nasal bridge, a longer than usual vertical indentation that extends from the middle area of the upper lip to the nose (philtrum), a thin upper lip and jawbone abnormalities like an abnormally small jaw (micrognathia) or the lower jawbone set further back than expected on the face (retrognathia). More common in individuals affected by GPS are prominent eyes (proptosis), a cone-head shaped head and a nose with either a bulbous end or a broad or prominent base. More common in individuals affected by SBBYS are immobile faces that show less expression (mask-like facies). Eye anomalies are also more frequent and can impact visual function including abnormalities of the ducts that supply tears to keep eyes moist (lacrimal ducts), drooping eyes (ptosis) and underdevelopment of eyelids (blepharophimosis) that prevent the eyelids from fully opening and permanently cover part of the eyes.
An opening at the top of the mouth (cleft palate) is present in about a third of individuals affected by KAT6B-related disorders. A few individuals with a cleft palate also have jawbone abnormalities and tongue displacement (glossoptosis) that form a cluster of features called Pierre Robin sequence. Tongue displacement can cause additional breathing, eating or swallowing difficulties in infants, but typically improves as the infant grows up.
Hearing loss is often present in individuals affected with KAT6B-related disorders. It can be caused by both sound waves incorrectly traveling through the ear (conductive) and damage to the inner ear or hearing nerves (sensorineural).
A minority of individuals with KAT6B-related disorders may have thyroid gland function abnormalities that cause less thyroid hormone to be produced (hypothyroidism). Some individuals may have an underdeveloped (hypoplasia) or absent (agenesis) thyroid gland.
Most individuals affected by KAT6B-related disorders have genital abnormalities. A male baby may be born with a urethra opening not at its usual location at the head of the penis (hypospadias) and may experience a delay or failure of the testes to descend into the scrotum (cryptorchidism). Females may have an enlarged clitoris and developmental abnormalities of the labia. Males with GPS are more likely to have developmental abnormalities of the scrotum, penis and testes and most females will have a delay in puberty.
Some individuals affected by KAT6B-related disorders can experience behavioral or psychiatric issues that can include anxiety, aggressive behavior, attention problems and features suggestive of autism spectrum disorder.
Kidney (renal) abnormalities occur in many individuals affected by GPS including kidney swelling, multiple cysts and functional anomalies that can rarely lead to kidney failure in infants.
Occasionally, teeth abnormalities may occur in affect individuals with KAT6B-related disorders and can include underdeveloped or absent teeth, a baby being born with teeth (natal teeth), and a child not losing their baby teeth as expected (retained primary dentition). A delay in the eruption of teeth tends to occur more in SBBYS.
KAT6B-related disorders are caused by a pathogenic variant (mutation) in the KAT6B gene. This gene is also known as the MORF or MYST4 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variant occurs, the protein that is created may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.
The KAT6B gene contains instructions for creating a type of protein (enzyme) that is classified as a histone acetyltransferase. Its function is to modify histones, which are structural proteins that bind to and tightly wrap DNA, similar to a spool wrapped with thread. Histones help to give chromosomes their signature shape. They also help to control when gene instructions are read (expressed) so the right proteins are produced at the right time for our bodies to function properly. By modifying histones, the KAT6B enzyme helps to control and regulate the expression of many other genes and their proteins throughout the body and, consequently, is involved in many aspects of health and development. A variation in the KAT6B gene that affects its enzyme’s ability to work correctly can lead to a wide range of health issues.
Researchers are finding that the location of a disease-causing variant within the KAT6B gene can be associated more often with either GPS or SBBYS (genotype-phenotype correlations). Variants that cause GPS are commonly found at the beginning of a set of instructions (exon) in the KAT6B gene called exon 18. It is suspected these variants may cause the KAT6B enzyme to gain the ability to function in inappropriate ways. Variants that cause SBBYS are commonly found at the end of exon 18 and within exons 3, 7, 11, or 14-17. It is suspected these variants may cause the KAT6B enzyme to lose its ability to function.
In cases where a variation in the KAT6B gene causes a disorder, it almost always occurs as a new (sporadic or de novo) mutation, which means it occurred randomly in that child without either parent having the mutation. Since the disorder is usually not inherited from or “carried” by a parent, it’s estimated there is a 1% risk of the mutation reoccurring in another child from the same parents.
If a person with a KAT6B-related disorder were to have a child, they could pass the altered KAT6B gene on to their children through autosomal dominant inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary for the appearance of the disease. The non-working gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the non-working gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
KAT6B-related disorders affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to the KAT6 Foundation, as of February 2023, there are 150 individuals around the world known to have a KAT6B gene variant. Rare disorders like KAT6B-related disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population but it is estimated that fewer than one in a million individuals may be affected.
A diagnosis of a KAT6B-related disorder is based upon identification of characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal diagnostic criteria have been established for KAT6B-related disorders, even if clinical features cause suspicion that an individual may have GPS or SBBYS. A diagnosis can only be confirmed through molecular genetic testing.
Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variants in the KAT6B gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having a KAT6B-related disorder for a type of molecular genetic test called whole exome sequencing (WES). WES examines the parts of genes that provide instructions to create proteins (exons) and evaluates all the exons within the genome (exome) at the same time. WES can then detect variants in the KAT6B gene or in other genes that may have overlapping clinical features. More recently, the KAT6B gene has been added to a molecular genetic test known as the intellectual disability next generation sequencing (NGS) panel. This test only examines genes throughout the genome that have known associations to intellectual disabilities. This more targeted approach means the test can be less expensive.
Affected individuals may undergo additional tests to assess the extent of the disease. Developmental examinations can help assess any developmental delays, including motor function and speech or language delays. Neuropsychological assessments can help evaluate brain function and its impact on cognition and behaviors. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects sometimes associated with the disorder. A test that measures electrical activity in the brain, called an electroencephalogram (EEG), may be recommended if seizures are a concern for the affected individual. Swallow tests to detect feeding issues, routine laboratory blood tests to evaluate kidney and thyroid function, and a physical exam to reveal abnormalities of the knees, muscles, genitalia or anus may also be conducted.
The treatment of KAT6B-related disorders is directed toward the specific symptoms that are apparent in each individual. There are no standardized treatment protocols or guidelines, but the coordinated efforts of a team of specialists can help tailor treatments to the affected individual. It is appropriate to routinely evaluate body systems affected by KAT6B-related disorders. Regular, routine evaluation by healthcare professionals can track symptoms as they change or develop over time and treatments can be adjusted by the appropriate to best support current needs.
Healthcare professionals that may be part of the care team can include pediatricians, surgeons and physicians who specialize in diagnosing and treating of developmental neurological disorders (neurologists) and disorders of the heart (cardiologists), eye (ophthalmologists), digestive system (gastroenterologists), musculoskeletal system (orthopedists), ears (otolaryngologists), kidneys (nephrologists), and thyroid (endocrinologists). Additionally, physical medicine and rehabilitation therapists (physical, occupational and speech therapists), developmental and neuropsychologists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also recommended.
At infancy and continuing at each clinic visit, feeding, breathing and swallowing issues should be evaluated and appropriately addressed. Feeding therapy may help resolve coordination or other feeding issues. A nasogastric or gastrostomy feeding tube, which delivers food directly to the stomach, may be most appropriate in some situations. Constipation can be severe and requires close on-going monitoring. Many children with congenital heart disease require corrective surgery.
Following an initial diagnosis, a developmental assessment may be performed, and appropriate physical medicine and rehabilitation therapies may be instituted. Mobility and flexibility can be addressed by physical and occupational therapy. In some cases, surgery to release muscles, orthopedic devices for proper positioning or durable medical devices for mobility assistance may be required. Behavioral concerns may be addressed by a developmental pediatrician. Speech therapy is often required. Affected children have benefited from the use of sign language and various communication devices. Additional medical, social, or vocational services including specialized learning programs may be necessary, including an individualized learning plan (IEP) and 504 plan that are updated regularly.
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