Frontometaphyseal dysplasia

Variants (also known as mutations) in  the FLNA gene have been identified in people with frontometaphyseal dysplasia. This condition is a member of a group of related conditions called otopalatodigital spectrum disorders, which also includes otopalatodigital syndrome type 1, otopalatodigital syndrome type 2, frontometaphyseal dysplasia, and Melnick-Needles syndrome (described  below). Frontometaphyseal dysplasia involves abnormalities in skeletal development, particularly involving the joints, and other health problems, including kidney, heart, and airway defects.

FLNA gene variants that cause frontometaphyseal dysplasia are described as "gain of function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Different variants in the FLNA gene appear to produce specific changes in the protein, resulting in particular signs and symptoms that are classified as individual FLNA-related disorders. Researchers suspect that the variants involved in frontometaphyseal dysplasia may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

Intestinal pseudo-obstruction

Several variants in the FLNA gene have been identified in people with intestinal pseudo-obstruction, a condition characterized by impairment of the muscle contractions that move food through the digestive tract (peristalsis).

The FLNA gene variants that cause intestinal pseudo-obstruction include deletions or duplications of genetic material. The variants are thought to reduce levels of the filamin A protein or impair its function; this type of variant is called "loss of function." Research suggests that decreased filamin A function may affect the shape of cells in the smooth muscles of the gastrointestinal tract during development before birth, causing abnormalities in the layering of these muscles. Smooth muscles line the internal organs; they contract and relax without being consciously controlled. Abnormal layering of these muscles may interfere with these musclar movements that move food through the digestive tract.

Deletions or duplications of genetic material can affect all or part of the FLNA gene, and may also include nearby genes on the X chromosome. Changes in these additional genes may account for some of the other signs and symptoms, such as neurological abnormalities and unusual facial features, that occur in some affected individuals.

Melnick-Needles syndrome

Several variants in a region of the FLNA gene called exon 22 have been identified in people with Melnick-Needles syndrome. This condition is typically the most severe of the otopalatodigital spectrum disorders (described above). It involves abnormalities in skeletal development, causing short stature, abnormal curvature of the spine, partial dislocation of joints, and other health problems. The FLNA gene variants associated with Melnick-Needles syndrome are described as "gain of function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Researchers believe that the variants involved in Melnick-Needles syndrome may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

Otopalatodigital syndrome type 1

Several variants in the FLNA gene have been found to cause otopalatodigital syndrome type 1. This condition is typically the mildest of the otopalatodigital spectrum disorders (described above). It is characterized by hearing loss caused by malformations in tiny bones in the ears (ossicles), an opening in the roof of the mouth (cleft palate), and skeletal abnormalities involving the fingers or toes (digits).

The FLNA gene variants that cause otopalatodigital syndrome type 1 all result in changes to the filamin A protein in a region that binds to actin (known as the CH2 domain). Many of these variants change single amino acids in the filamin A protein. These variants are described as "gain-of-function" because they appear to lead to a protein with an increased ability to bind to actin. Researchers believe that the FLNA gene variants impair the stability of the cytoskeleton and disrupt cellular processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of otopalatodigital syndrome type 1.

Otopalatodigital syndrome type 2

Several variants in the FLNA gene have been found to cause otopalatodigital syndrome type 2, which is part of the otopalatodigital spectrum (described above). This condition is similar to otopalatodigital syndrome type 1 (described above) and is characterized by hearing loss caused by malformations in the ossicles, a cleft palate, and skeletal abnormalities involving the digits. These abnormalities in skeletal development are typically more severe than in otopalatodigital syndrome type 1.

The FLNA gene variants that cause otopalatodigital syndrome type 2 all result in changes to the filamin A protein in a region that binds to actin (known as the CH2 domain). Most of these variants change single amino acids in the filamin A protein. These variants are described as "gain-of-function" because they appear to lead to a protein with an increased ability to bind to actin. Researchers believe that the FLNA gene variants impair the stability of the cytoskeleton and disrupt cellular processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of otopalatodigital syndrome type 2.

Periventricular heterotopia

Hundreds of FLNA gene variants have been identified in individuals with periventricular heterotopia, a condition in which nerve cells (neurons) do not move (migrate) properly during the early development of the fetal brain leading to seizures and other neurological problems. Most of these variants result in a lack of filamin A protein, which makes the cytoskeleton disorganized and impairs the attachment (adhesion) of cells to one another. Impaired adhesion alters cells that line the fluid-filled cavities near the center of the brain (the ventricles), which is where neurons develop. Disruption of this lining prevents the movement of neurons to the surface of the brain. Neurons that do not migrate properly during development form clumps (nodules) around the ventricles, resulting in the signs and symptoms of periventricular heterotopia.

In some cases, variants result in the substitution of one protein building block (amino acid) for another amino acid in the protein sequence. These variants may result in the production of a partially functional protein, sometimes causing a milder form of the disorder.

Terminal osseous dysplasia

At least one variant in the FLNA gene has been found to cause terminal osseous dysplasia, which is part of the otopalatodigital spectrum of disorders (described above). Terminal osseous dysplasia is characterized by skeletal abnormalities in the hands and feet, noncancerous (benign) tumors on the fingers and toes (digits), and dark patches of skin on the face. 

The FLNA gene variant that causes terminal osseous dysplasia changes a single DNA building block (nucleotide) in the gene, substituting adenine for guanine at DNA position 5217 (written as 5217G>A). This DNA change alters the way the blueprint for making the filamin A protein is put together. The version of the protein made using this blueprint is abnormally short. Researchers suspect the altered protein may not be able to interact with other molecules normally. It is thought that the inability to bind to other proteins disrupts important processes involved in skeletal development and cell growth, leading to the bone and skin abnormalities characteristic of terminal osseous dysplasia.

X-linked cardiac valvular dysplasia

Variants in the FLNA gene have been found to cause X-linked cardiac valvular dysplasia, a condition characterized by abnormally thick heart valves. Most of these variants change single amino acids in the filamin A protein. These variants likely alter the shape of the protein, impairing its ability to bind to actin and other proteins. As a result, the cell cytoskeleton is weakened and valve cells and the extracellular matrix are disorganized. The cells are not positioned properly within the valve, so the valve becomes malformed. In addition, the cells' decreased ability to change shape impairs the valves' ability to open and close when the heart pumps blood. It appears that excess proteins are produced in the abnormal extracellular matrix, causing the valves to become thickened and further impairing their ability to open and close normally.

It is unclear why the heart valves are the only tissue affected by these FLNA gene variants. The variants that cause X-linked cardiac valvular dysplasia occur in a different part of the gene than those that cause other disorders (described above). It has been suggested that the region of the filamin A protein affected by these variants is necessary for binding to other proteins that play a significant role in heart development.

FG syndrome

MedlinePlus Genetics provides information about FG syndrome