Duchenne muscular dystrophy inheritance
Reviewed by Duchenne muscular dystrophy (DMD) is an inheritable condition, which means it can be passed down from parents to children through genes. DMD is characterized by progressive muscle wasting (atrophy) and weakness of the skeletal and heart muscles, leading to declining muscle function and heart problems.
The disease is caused by a mutation in the DMD gene, the largest in the human genome, which provides instructions for making dystrophin, a protein that protects muscles during contraction. Without it, muscle cells become damaged and eventually die.
How is Duchenne muscular dystrophy inherited?
DMD usually occurs when a mother passes an altered gene to her son, although there are also very rare cases of DMD being passed from a mother to her daughter. The way DMD is passed from one generation to the next is a bit complicated.
Genes are organized on chromosomes: long, tightly packaged pieces of DNA. We typically have 23 pairs of chromosomes. Chromosome pairs 1 to 22 carry the same genes. The final pair, the sex chromosomes, differ: Females typically inherit an X chromosome from each parent, while males typically inherit an X from their mother and a Y from their father.
What does X-linked inheritance mean?
The DMD gene is located on the X chromosome, so DMD is an X-linked condition that mostly affects males, who have only one X chromosome.
How Duchenne is passed from a carrier mother
Because females have two X chromosomes, the second X chromosome can compensate for the mutated DMD gene by producing enough dystrophin protein to prevent or cause only mild DMD symptoms, while a small number can be more noticeably affected. Females who have one mutated copy of the DMD gene and one normal copy of the DMD gene are called DMD carriers and can pass the disease to their children, most often without having symptoms themselves.
A Duchenne carrier mother has a 50% chance of passing the gene mutation to a child. A son who inherits it will have DMD, while a daughter will be a carrier who may or may not have symptoms.
How Duchenne is passed from an affected father
Because DMD is X-linked, a man with DMD cannot pass it to his sons, who inherit his Y chromosome. Each daughter inherits his affected X chromosome and will be a carrier who may pass the variant to her children.
What are the chances of passing Duchenne to a child?
Having the DMD gene mutation and developing the disease are two different things.
The table below explains the risk of a child inheriting and developing DMD, which is dependent on whether the gene comes from the father or the mother.
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| Parent with a mutated gene | Child’s sex | Child’s risk of inheriting a mutated gene | Outcome for the child |
| Mother (carrier) | son | 50% | If mutated gene is inherited, DMD will develop |
| Mother (carrier) | daughter | 50% | Becomes a carrier; may be asymptomatic or develop symptoms |
| Father (has DMD) | son | 0% | Does not inherit gene; unaffected |
| Father (has DMD) | daughter | 100% | Becomes a carrier; may be asymptomatic or develop symptoms |
Can Duchenne occur without a family history?
DMD can develop without a family having or being aware of an altered DMD gene.
De novo DMD mutations
Around 1 in 3 DMD cases develop due to a new DMD gene change that was not previously identified in the family. These are known as spontaneous, or de novo, DMD mutations.
Some families may simply not be aware of their DMD family history. If the females in the family had the mutated gene but not the males, it means they may have been carriers without realizing. Alternatively, if males in the family had developed DMD several generations ago, the medical capabilities at the time may not have been able to identify the disease or the gene.
As prenatal genetic testing becomes more common and family planning reduces the number of inherited cases, de novo DMD is starting to catch up to inherited DMD in terms of how many people have it.
Germline mosaicism
Germline mosaicism is another possible factor. While most carriers have DMD mutations in every cell of their body, females with germline mosaicism have the pathogenic DMD variant only in some of their egg cells, but not in other cells in the body. Because genetic tests usually check saliva or blood, they can miss germline mosaicism and come back negative. It is impossible to know how many egg cells are affected.
As routine lab testing cannot identify it, healthcare professionals deduce that germline mosaicism explains most cases where a woman has no DMD mutation on blood testing but has at least one child with DMD. Research has found evidence for germline mosaicism in an average of just over 8% of families with a de novo DMD variant.
A woman is unlikely to have health problems resulting from germline mosaicism, as the rest of her cells have two functional copies of the DMD gene. However, the same research found that a woman with a negative carrier test but one affected son has a 4.3-11% risk of having another son with DMD.
What does being a female DMD carrier mean?
Being a female DMD carrier means you can pass on the gene to your offspring, as you have one X chromosome carrying the mutation. You have a 50% chance of passing on the mutation in each pregnancy.
Most carriers do not have any symptoms themselves. However, carriers can still develop symptoms of dystrophinopathy — a group of conditions including DMD, but also milder forms such as Becker muscular dystrophy, that cause muscle weakness or heart problems due to issues with dystrophin production. Female carriers who have symptoms are known as manifesting carriers.
Possible symptoms
Female carriers may experience the following symptoms, which can range from mild to severe:
- Muscle weakness and other symptoms: Weakness usually begins in the hips and thighs in adulthood, making it harder to walk, run, or climb stairs. It may slowly spread to the shoulders and arms, although severe weakness is rare. Enlarged calves, muscle pain, and fatigue may also occur.
- Heart problems: Carriers have a risk of heart muscle weakness, known as cardiomyopathy, which can develop even without accompanying muscle weakness. Cardiomyopathy may cause dizziness or shortness of breath. It requires regular monitoring and management with medication.
- Breathing problems: A carrier may experience mild breathing issues, such as reduced lung capacity or a weak cough due to weakened respiratory muscles.
- Neurodevelopmental challenges: Manifesting carriers may experience learning difficulties and behavioral conditions due to dystrophin’s role in brain function.
Heart monitoring and other care for female DMD carriers
Carriers should see a cardiologist, even if they are not aware of heart symptoms. Diagnosis as a carrier should lead to timely cardiology referral. Depending on the individual’s symptoms and needs, additional specialists, including a neuromuscular specialist, may also play roles in care, helping to manage muscle problems and other issues.
Female carriers who are considering pregnancy may benefit from consulting a prenatal genetic counselor to discuss their reproductive options and recurrence risk, and seek practical and emotional support.
Who should consider DMD carrier testing?
Genetic testing is the most reliable method for determining whether or not a woman is a carrier. Good candidates for carrier testing include women with a family history of dystrophinopathy, specifically those with the following:
- brothers or sons who have a dystrophinopathy diagnosis
- sisters or mothers who are confirmed carriers
- uncles or cousins in their mother’s family who live with dystrophinopathy
- maternal aunts or female cousins who are carriers
Females who experience specific symptoms can also consider carrier testing, including:
- unexplained muscle symptoms
- unexplained heart/cardiac symptoms
- unexplained elevated creatine kinase levels
Once a diagnosis of dystrophinopathy is confirmed in a family, a genetic counselor can help family members determine whether they would benefit from genetic testing.
What reproductive and family planning options are available?
People with an increased risk of having a child with DMD have several reproductive options depending on how a pregnancy is conceived and what genetic tests are used:
- Natural conception: Carriers can conceive naturally, with or without prenatal genetic testing. A child can also be tested for the DMD gene variant after birth.
- Assisted reproductive technologies: In-vitro fertilization (IVF) can be combined with preimplantation genetic testing to screen embryos before transfer.
- Egg and sperm donation: Donor eggs from a non-carrier can avoid transmission from a carrier mother. Males with DMD can use donor sperm to reduce the chance of having carrier daughters.
- Adoption: Adoption offers a way to build a family without passing on dystrophinopathy.
Testing before pregnancy
If a family has a confirmed DMD diagnosis but the specific disease-causing variant is unknown, linkage analysis can track the at-risk X chromosome. It requires blood samples from multiple family members, including affected individuals, so arranging it before pregnancy is encouraged.
Those considering donor eggs or sperm should review the donor’s genetic screening, including testing for DMD variants.
Testing during pregnancy
Prenatal testing can assess chromosomal sex and the inherited DMD variant. Chorionic villus sampling (CVS) and amniocentesis are invasive and carry a small risk of complications, including miscarriage.
- CVS: Usually performed at 10-12 weeks, it tests placental tissue that shares the fetus’s genetic makeup.
- Amniocentesis: Performed from 15 weeks onward, it tests fetal cells in amniotic fluid.
- Noninvasive prenatal testing/screening: A maternal blood test can screen for sex chromosomes and certain genetic conditions, but may not test for the DMD variant.
Preimplantation genetic diagnosis
With IVF, preimplantation genetic diagnosis (PGD) tests cells from embryos before transfer. Direct testing for a DMD variant may depend on samples from other family members; when it is unavailable, testing may still screen for chromosomal sex.
PGD is not 100% accurate and may not be covered by insurance. CVS or amniocentesis is often recommended to confirm the result.
Genetic counseling for Duchenne
A DMD diagnosis may raise questions about your child’s health, whether you are a carrier, whether you can have more children, and who else in your family may be affected.
Sharing test results with relatives can be difficult. If a mutation is traced to a grandmother or great-grandmother, her living sisters and their female descendants may also qualify for testing.
Potentially affected family members should consult a genetic counselor, who can review family history, coordinate testing, interpret results, and offer emotional support.
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