CLCN4-Related Syndrome

CLCN4-related syndrome happens when there are changes in the CLCN4 gene. These changes can keep the gene from working as it should.

The CLCN4 gene is located on the X chromosome, which is one of the sex chromosomes. Chromosomes are structures in our cells that house our genes.

CLCN4-related syndrome usually happens in males, but females may also have the condition. This depends on the type of genetic variant found in females. A female biological CLCN4-carrier parent may have mild neurodevelopmental features.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.

The risk of having another child who has CLCN4-related syndrome depends on the genes of both biological parents.

X-linked recessive conditions

• Biological females who have a variant in the CLCN4 gene and are pregnant with a daughter have a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene.
• If they are pregnant with a son, the child has a 50 percent chance of inheriting the genetic variant and the syndrome.

For a symptom-free brother or sister of someone who has CLCN4-related syndrome, the sibling’s risk of having a child who has CLCN4-related syndrome depends on the sibling’s genes and their parents’ genes.

• If neither parent has the same genetic variant causing CLCN4-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit CLCN4-related syndrome.
• If the biological mother has the same genetic variant causing CLCN4-related syndrome, and the symptom-free daughter has the variant, the symptom-free daughter’s chance of having a son who has CLCN4-related syndrome is 50 percent.

For a person who has CLCN4-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

X-linked dominant conditions

• For a biological female parent who does not have the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increased risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant.
• For a biological female parent who has the same CLCN4 variant and is pregnant with a daughter, there is a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene without the same CLCN4 genetic variant.
• If they are pregnant with a son, there is a 50 percent chance of passing on the same genetic variant and the syndrome.

For a symptom-free brother or sister of someone who has CLCN4-related syndrome, the sibling’s risk of having a child who has CLCN4-related syndrome depends on the sibling’s genes and their parents’ genes.

• If neither parent has the same genetic variant causing CLCN4-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit CLCN4-related syndrome.
• If the biological mother has the same genetic variant causing CLCN4-related syndrome, the symptom-free daughter has a 50 percent chance of also having the same genetic variant. If the symptom-free daughter has the same genetic variant as their sibling who has the syndrome, the symptom-free sibling’s chance of having a son who has CLCN4-related syndrome is 50 percent.

For a person who has CLCN4-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2025, about 146 people with CLCN4-related syndrome have been identified in medical research.

Young children who have CLCN4-related syndrome do not usually look different, but as people get older, they may look a bit different. Older people may have some but not all of these features:

• Long face with straight nose
• Pointed chin
• Flat midface
• Square jaw shape

Scientists and doctors have only just begun to study CLCN4-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

• Physical exams and brain studies
• Genetics consults
• Development and behavior studies
• Other issues, as needed

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

• Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
• Guide individualized education plans (IEPs).

Specialists advise that therapies for CLCN4-related syndrome should begin as early as possible, ideally before a child begins school.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: www.epilepsy.com/learn/types-seizures.

The information below is grouped by 1) males with a CLCN4 genetic variant, 2) females with a new (also called de novo) CLCN4 genetic variant that did not come from either parent, and 3) females with an inherited CLCN4 genetic variant, or with a variant of unknown inheritance.

1) Males with a CLCN4 genetic variant

Speech and Learning

Males had developmental delay or intellectual disability (ID), and speech delays or impairment. A few males did not have a reported intellectual disability, but they had a learning disability.

• 71 out of 73 people had developmental delay or intellectual disability (97 percent)
• 70 out of 70 people had speech impairment (100 percent)

The severity of intellectual disability (ID) varied among people:

• 16 out of 67 people had mild or borderline ID (24 percent)
• 22 out of 67 people had moderate ID (33 percent)
• 29 out of 67 people had severe or profound ID (43 percent)

Behavior

Males had behavioral issues, such as autism, attention-deficit/hyperactivity disorder (ADHD), aggression or outbursts, anxiety, obsessive-compulsive disorder, sleep challenges, and psychotic disorder.

• 20 out of 72 people had autism (28 percent)
• 17 out of 58 people had ADHD (29 percent)
• 8 out of 58 people had aggression or outbursts (14 percent)
• 10 out of 58 people had anxiety (17 percent)
• 6 out of 58 people had obsessive-compulsive disorder (10 percent)
• 1 out of 58 people had psychotic disorder (2 percent)

Brain

Males had neurological medical issues, including seizures, brain changes seen on magnetic resonance imaging (MRI), lower than average muscle tone (hypotonia), and a smaller than average head size (microcephaly).

• 45 out of 73 people had seizures (62 percent)
• 31 out of 47 people had brain changes seen on MRI (66 percent)
• 23 out of 61 people had hypotonia (38 percent)
• 11 out of 59 people had microcephaly (19 percent)

About 3 out of 10 males (32 percent) had late onset of neurological symptoms, such as tremor, ataxia, abnormally increased and sometimes uncontrollable activity or muscular movements, stereotypical movements, and changes in walking over time.

2) Females with a new CLCN4 genetic variant

Speech and Learning

Most females with a new CLCN4 genetic variant had developmental delay or intellectual disability (ID), and speech delays or impairment.

• 22 out of 24 people had developmental delay or intellectual disability (92 percent)
• 23 out of 24 people had speech impairment (96 percent)

The severity of intellectual disability (ID) varied among people:

• 8 out of 20 people had mild or borderline ID (40 percent)
• 8 out of 20 people had moderate ID (40 percent)
• 4 out of 20 people had severe or profound ID (20 percent)

Behavior

Females with a new CLCN4 genetic variant had behavioral issues, such as autism, attention-deficit/hyperactivity disorder (ADHD), aggression or outbursts, anxiety, obsessive-compulsive disorder, and sleep challenges.

• 6 out of 23 people had autism (26 percent)
• 7 out of 20 people had ADHD (35 percent)
• 6 out of 20 people had aggression or outbursts (30 percent)
• 9 out of 20 people had anxiety (45 percent)
• 2 out of 20 people had obsessive-compulsive disorder (10 percent)

Brain

Females with a new CLCN4 genetic variant had neurological medical issues, including seizures, brain changes seen on magnetic resonance imaging (MRI), and lower than average muscle tone (hypotonia).

• 6 out of 24 people had seizures (25 percent)
• 12 out of 20 people had brain changes seen on MRI (60 percent)
• 11 out of 20 people had hypotonia (55 percent)

Most females were able to control seizures with medication.

• 5 out of 6 people had seizures controlled with medication (83 percent)

Exactly 4 out of 10 females (40 percent) had late onset neurological symptoms, such as tremor, ataxia, abnormally increased and sometimes uncontrollable activity or muscular movements, stereotypical movements, and changes in walking over time.

3) Females with an inherited CLCN4 genetic variant, or a variant of unknown inheritance

Speech and Learning

Some females had developmental delay or intellectual disability (ID), and speech delays or impairment.

• 12 out of 47 people had developmental delay or intellectual disability (26 percent)
• 7 out of 47 people had speech impairment (15 percent)

The severity of intellectual disability (ID) varied among people:

• 6 out of 47 people had mild or borderline ID (13 percent)
• 1 out of 47 people had moderate ID (2 percent)
• 5 out of 47 people had severe or profound ID (11 percent)

Behavior

Some females had behavioral issues, such as autism, attention-deficit/hyperactivity disorder (ADHD), anxiety, and depression or bipolar disorder.

• 5 out of 37 people had autism (14 percent)
• 3 out of 37 people had ADHD (8 percent)
• 3 out of 37 people had anxiety (8 percent)
• 3 out of 37 people had depression or bipolar disorder (8 percent)

Brain

Rarely, females had neurological medical issues, including seizures and lower than average muscle tone (hypotonia).

• 2 out of 44 people had seizures (5 percent)
• 3 out of 37 people had hypotonia (8 percent)

Cure CLCN4

Cure CLCn4 is a registered charity aimed at providing support, raising awareness and funding medical research for effective treatments for CLCN4.

• https://cureclcn4.org/

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

• Learn more about Simons Searchlight: www.simonssearchlight.org/frequently-asked-questions

• Simons Searchlight webpage with more information on CLCN4: www.simonssearchlight.org/research/what-we-study/clcn4

• Simons Searchlight CLCN4 Facebook community: https://www.facebook.com/groups/clcn4