GENE GUIDE

NEXMIF-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has NEXMIF-Related Syndrome.
a doctor sees a patient

NEXMIF-related syndrome is also called intellectual developmental disorder, X-linked 98. For this webpage, we will be using the name NEXMIF-related syndrome to encompass the wide range of variants observed in the people identified.

NEXMIF-related syndrome happens when there are changes in the NEXMIF gene. These changes can keep the gene from working as it should. The NEXMIF gene was previously called KIAA2022.

Key Role

The NEXMIF gene plays a key role in brain cell growth.

Symptoms

Because the NEXMIF gene is important for brain activity, many people who have NEXMIF-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Language delay
  • Seizures
  • Movement issues, such as ataxia or unstable walking
  • Autism
  • Attention-deficit/hyperactivity disorder (ADHD)
  • Gastroesophageal reflux disease (GERD)
  • Smaller than average head size, also called microcephaly
  • Lower than average muscle tone

NEXMIF-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother’s egg, and one copy from the father’s sperm. 

We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father. 

In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both. 

The NEXMIF gene is located on the X chromosome, therefore variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have NEXMIF-related syndrome. 

Biological females who have variants in this gene may or may not have symptoms of NEXMIF-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.

X-linked dominant conditions

NEXMIF-related syndrome usually results from a spontaneous variant in the NEXMIF gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene variant. 

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because NEXMIF plays a key role in development, de novo variants in this gene can have a meaningful effect. Many parents who have had their genes tested do not have the NEXMIF gene variant found in their child who has the syndrome.

In some cases, NEXMIF-related syndrome is inherited. Biological females who inherit the NEXMIF gene variant tend to have milder symptoms than those who have a de novo variant.

X-Linked Dominant Genetic Syndrome

Sex chromosomes
Non-carrier father
Non-carrier mother
Sex chromosomes
Genetic variant happens in X-chromosome in sperm or egg, or after fertilization
Non-carrier female
Female child with X-linked genetic condition
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child have a change in the NEXMIF gene?

No parent causes their child’s NEXMIF-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.

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 NEXMIF-related syndrome depends on the genes of both biological parents. 

  • 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 NEXMIF 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 NEXMIF 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 NEXMIF-related syndrome, the sibling’s risk of having a child who has NEXMIF-related syndrome depends on the sibling’s genes and their parents’ genes. 

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

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

As of 2024, about 189 people with NEXMIF-related syndrome have been identified in a medical clinic. The first case of NEXMIF-related syndrome was described in 2014. Scientists expect to find more people who have the syndrome as access to genetic testing improves.

People who have NEXMIF-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Smaller than average head size
  • Large ears
  • Low muscle tone face
  • Round face shape
  • Lower than average muscle tone

Scientists and doctors have only just begun to study NEXMIF-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 NEXMIF-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: epilepsy.com/…t-is-epilepsy/seizure-types

This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

Females have two X chromosomes and two copies of the NEXMIF gene, whereas males have one X chromosome and one copy of the NEXMIF gene.

Female carriers have slightly different medical features than males. This may be due to what is called X inactivation, which is a random process where a cell chooses one X chromosome to silence gene expression. If the affected X chromosome is inactivated, this means that the NEXMIF variant would be silenced or turned off.

For some females, the unaffected X chromosome is inactivated, resulting in a person having more medical features.

Males with NEXMIF-related syndrome

Speech and Learning

Males with NEXMIF-related syndrome had developmental delay or intellectual disability and speech issues.

  • 23 out of 23 people had developmental delay or intellectual disability (100 percent)
  • 10 out of 12 people had speech issues (83 percent)

For males with intellectual disability:

  • 7 out of 23 people had profound intellectual disability (30 percent)
  • 10 out of 23 people had severe intellectual disability (44 percent)
  • 6 out of 23 people had mild to moderate intellectual disability (26 percent)
30%
7 out of 23 people had profound intellectual disability.
44%
10 out of 23 people had severe intellectual disability.
26%
6 out of 23 people had mild to moderate intellectual disability.

Behavior

Behavioral disorders occurred in males with NEXMIF-related syndrome, including features of autism.

  • 19 out of 23 people had behavioral issues (83 percent)
  • 18 out of 23 people had features of autism (78 percent)

Brain

Many males with NEXMIF-related syndrome had seizures, with an age of onset around 15 months old. But, males had developed seizures as young as 1 month old and as old as 14 years old. The most common seizure types were myoclonic and absence seizures.

Most brain imaging showed normal or minor findings. Some people had defects, including regional or generalized brain atrophy.

  • 15 out of 23 people had seizures (65 percent)
  • 10 out of 78 people had brain changes on MRI (13 percent)

Females with NEXMIF-related syndrome

Speech and Learning

Females with NEXMIF-related syndrome had developmental delay or intellectual disability and speech issues.

  • 60 out of 61 people had developmental delay or intellectual disability (98 percent)
  • 14 out of 52 people had speech issues (27 percent)

For females with intellectual disability:

  • 1 out of 60 people had profound intellectual disability (2 percent)
  • 18 out of 60 people had severe intellectual disability (30 percent)
  • 41 out of 60 people had mild to moderate intellectual disability (68 percent)
Human head showing brain outline
2%
1 out of 60 people had profound intellectual disability.
30%
18 out of 60 people had severe intellectual disability.
68%
41 out of 60 people had mild to moderate intellectual disability.

Behavior

Behavioral disorders occurred in females with NEXMIF-related syndrome, including features of autism.

  • 41 out of 61 people had behavioral issues (67 percent)
  • 28 out of 61 people had features of autism (46 percent)

Brain

Most females with NEXMIF-related syndrome had seizures, with an age of onset around 19 months old. But, females had developed seizures as young as 1 month old and as old as 17 years old. The most common seizure types were myoclonic and absence seizures.

Most brain imaging showed  normal or minor findings. Some people had defects, including regional or generalized brain atrophy.

  • 56 out of 63 people had seizures (89 percent)
  • 10 out of 78 people had brain changes on MRI (13 percent)

Male and Female Adults

About one-half of adults were overweight or obese. Some people had a dysfunction of the hypothalamic–pituitary system, such as hypogonadotropic hypogonadism, central hypothyroidism, precocious puberty, primary amenorrhea, and delayed bone age.

  • 11 out of 18 females were overweight or obese (61 percent)
  • 2 out of 5 males were overweight or obese (40 percent)

Where can I find support and resources?

XLID98 Foundation

The goal of the XLID98 Foundation is to support families of individuals affected by XLID98 (also known as KIAA2022/NEXMIF/MRX98) worldwide.
Their hope is to establish a supportive community, educate families, foster collaborations with physicians, scientists and other patient advocacy organizations.  They will also be raising awareness and supporting medical research, helping children diagnosed with this rare condition get the treatment they need to improve their quality of life.

XLID98 / KIAA2022 / NEXMIF / MRX98 Facebook Group

Unione Italiana Nexmif

Unione Italiana Nexmif is a volunteer organization dedicated to people diagnosed with mutation in the gene Nexmif, with the dream of a cure.

NEXMIF ITALIA odv

NEXMIF ITALIA odv is an association dedicated to research and support for people affected by rare genetic diseases such as the NEXMIF gene mutation

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.”

 

Sources and References

  • de Lange IM. et al. Journal of Medical Genetics, 53, 850-858, (2016). De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy, www.ncbi.nlm.nih.gov/pmc/articles/PMC5264224.
  • Stamberger H. et al. Genetics in Medicine, Epub ahead of print, (2020). NEXMIF encephalopathy: An X-linked disorder with male and female phenotypic patterns, www.nature.com/articles/s41436-020-00988-9.
  • Stamberger, H., Hammer, T. B., Gardella, E., Vlaskamp, D. R. M., Bertelsen, B., Mandelstam, S., de Lange, I., Zhang, J., Myers, C. T., … & Scheffer, I. E. (2021). NEXMIF encephalopathy: An X-linked disorder with male and female phenotypic patterns. Genetics in Medicine, 23(2), 363-373. https://pubmed.ncbi.nlm.nih.gov/33144681/

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