DMD Pedigree: Key Insights on Genetic Transmission

Duchenne muscular dystrophy (DMD) is a severe genetic disorder that primarily affects boys, leading to progressive muscle degeneration and weakness. Understanding its inheritance helps families assess risk, guide medical decisions, and make informed reproductive choices. Pedigree analysis plays a crucial role in identifying inheritance patterns within affected families.

By examining family history through standardized symbols, researchers and healthcare providers can pinpoint carriers and predict potential cases.

Mechanisms Of Genetic Transmission

DMD follows an X-linked recessive inheritance pattern, meaning the mutation responsible is located on the X chromosome. Since males have only one X chromosome, a single defective copy of the dystrophin gene causes the disease. Females, with two X chromosomes, typically remain asymptomatic carriers unless skewed X-inactivation leads to partial expression. This explains why DMD primarily affects boys while being silently passed through maternal lineages.

The dystrophin gene, one of the largest in the human genome, is highly susceptible to mutations, with deletions, duplications, and point mutations contributing to disease onset. About two-thirds of DMD cases result from inherited mutations, while the remaining third arise from spontaneous genetic alterations. This high rate of new mutations complicates genetic counseling, as families with no prior history of DMD can still have affected children due to de novo mutations.

Maternal carriers have a 50% chance of passing the mutation to each son, who, if affected, will develop the disease. Daughters of carriers have the same probability of inheriting the mutation but typically do not exhibit symptoms due to a functional dystrophin gene on their second X chromosome. However, some female carriers experience mild muscle weakness or cardiomyopathy due to variable X-chromosome inactivation. Advanced genetic testing, including multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS), has improved mutation detection, allowing for more precise risk assessments.

Reading Pedigree Symbols

Interpreting pedigree symbols is essential when analyzing DMD inheritance. Standardized symbols provide a visual representation of how genetic traits pass through generations. Squares denote males, circles represent females, and shaded figures indicate affected individuals. Carriers—typically females in X-linked recessive disorders—may be marked with a dot or partial shading to differentiate them from symptomatic individuals.

Connecting lines clarify relationships. A horizontal line between a square and a circle signifies a mating pair, with vertical lines extending downward to offspring. Siblings are arranged from left to right in birth order. In a DMD pedigree, affected males appearing across generations through maternal lines strongly suggest an X-linked recessive pattern. The absence of male-to-male transmission reinforces this diagnosis, as fathers only pass a Y chromosome to their sons, making it impossible for them to transmit an X-linked mutation.

Carrier identification within a pedigree requires careful examination of female relatives. Unaffected mothers of affected sons are presumed carriers unless proven otherwise through genetic testing. Sisters of affected males have a 50% probability of carrying the mutation if their mother is a confirmed carrier. In some cases, obligate carriers can be identified without direct testing—such as when a woman has two affected sons or an affected brother and son. Recognizing these patterns allows genetic counselors to estimate recurrence risks and guide family planning.

Identifying X-Linked Recessive Inheritance

Tracing DMD inheritance requires understanding X-linked recessive patterns. Since the dystrophin gene is on the X chromosome, males with a single defective copy develop symptoms, while females, with two X chromosomes, are typically protected by a functional copy. This results in a pedigree pattern where affected individuals are almost exclusively male, and transmission occurs through maternal carriers rather than father to son.

A key characteristic of X-linked recessive inheritance is the absence of male-to-male transmission. Fathers pass their Y chromosome to sons, meaning an affected male cannot transmit the disease to his male offspring. Instead, affected males can only pass the mutation to their daughters, who inherit the defective gene on one X chromosome while receiving a normal copy from their mother. These daughters become obligate carriers, capable of passing the mutation to future generations. If a carrier woman has children, each son has a 50% chance of inheriting the affected gene and developing the condition, while each daughter has the same probability of becoming a carrier.

Molecular Basis Of The Dystrophin Gene

The dystrophin gene, located on the X chromosome at position Xp21.2, is one of the largest known human genes, spanning approximately 2.2 million base pairs. Its size makes it particularly vulnerable to mutations, which can disrupt the production of dystrophin, a protein essential for maintaining the structural integrity of muscle fibers. Dystrophin connects the cytoskeleton of muscle cells to the extracellular matrix through the dystrophin-glycoprotein complex, stabilizing muscle membranes during contraction and relaxation. Without functional dystrophin, muscle cells become susceptible to mechanical stress, leading to progressive degeneration and fibrosis.

Mutations in the dystrophin gene include large deletions, duplications, and small point mutations. Deletions account for about 60–70% of DMD cases, often disrupting the reading frame and resulting in a nonfunctional protein. The reading frame hypothesis, first proposed by Monaco et al. in 1988, explains why out-of-frame mutations cause DMD, while in-frame mutations typically result in the milder Becker muscular dystrophy (BMD). Advances in genetic sequencing, such as MLPA and NGS, have improved mutation detection, facilitating early diagnosis and carrier identification.

Clinical Indicators In Familial Clusters

Recognizing DMD patterns within families can provide early diagnostic clues, especially when a known mutation has not yet been identified. The most telling indicator is progressive muscle weakness in young male relatives, typically appearing between ages two and five. Affected boys often experience delays in motor milestones, such as standing or walking, and have difficulty climbing stairs or rising from the floor, a hallmark sign known as Gower’s maneuver. These symptoms worsen as muscle degeneration progresses.

Beyond affected males, familial clusters may reveal subtle signs in female carriers. While traditionally considered asymptomatic, some carriers develop mild muscle weakness or cardiac complications, particularly dilated cardiomyopathy, which can emerge in adulthood. Echocardiographic screening in known carriers has demonstrated left ventricular dysfunction in some individuals, reinforcing the need for cardiac monitoring. Elevated serum creatine kinase (CK) levels in female relatives can also indicate carrier status, even in the absence of symptoms. Identifying these indicators within a pedigree allows for earlier intervention and better medical management.

Carrier Testing Approaches

Assessing carrier status in females with a family history of DMD is crucial for genetic counseling, as it helps determine reproductive risks and guides clinical monitoring. Carrier testing typically begins with biochemical screening, specifically measuring serum creatine kinase (CK) levels. Elevated CK concentrations indicate muscle membrane instability, a common feature in carriers due to partial dystrophin deficiency. However, CK testing alone is insufficient for definitive carrier identification, as levels can vary widely and may be normal in some carriers despite harboring a mutation.

Genetic testing provides a more precise approach, with MLPA and NGS serving as primary methods for detecting dystrophin gene mutations. MLPA effectively identifies large deletions and duplications, which account for most DMD mutations, while NGS offers comprehensive analysis, including detection of point mutations and small insertions or deletions. In cases where a known familial mutation has been identified, targeted testing can confirm carrier status with high accuracy. For women without a clear family history but with an affected son, de novo mutations must be considered, necessitating additional testing to determine recurrence risk.