Does Dementia Skip a Generation?

[Anonymous]

Does Dementia Skip a Generation?

[Genetic Counselor]

Families sometimes notice that one generation appears healthy even though several other relatives have dementia.

This raises an important question: Can dementia skip a generation?

The answer depends on the type of genetic condition and its inheritance pattern.

Understanding Autosomal Dominant Inheritance

Autosomal dominant inheritance means that a pathogenic variant in just one copy of a particular gene can cause a genetic condition.

Familial Alzheimer’s disease can be associated with APP, PSEN1 and PSEN2. Familial frontotemporal dementia can be associated with MAPT, GRN and C9orf72.

If an individual carries a heterozygous pathogenic variant in one of these genes, each biological child has a 50% chance of inheriting that variant.

Consider the following family:

Generation I: Grandfather has a pathogenic variant and develops dementia at 55.

Generation II: His daughter inherits the variant but has not developed symptoms at age 40.

Generation III: Her son inherits the same variant.

The family may initially believe that dementia has skipped Generation II because the daughter appears healthy.

However, she may still be at risk of developing symptoms later in life.

The genetic variant has not skipped a generation. The clinical symptoms simply have not appeared yet.

What Is Reduced Penetrance?

Penetrance refers to the proportion of individuals carrying a particular genetic variant who develop the associated clinical condition.

Some variants show reduced or age-dependent penetrance.

This means that:

Some carriers may develop symptoms relatively early.
Others may develop symptoms much later.
Some carriers may never develop the expected clinical condition.

Therefore, an apparently unaffected parent may still carry a pathogenic variant.

What If There Is No Family History?

A person can occasionally develop genetic dementia even when no other family member is known to have the condition.

Possible explanations include:

De novo variant: A new genetic change that is not detected in either biological parent.

Early death: A parent may have died before reaching the usual age of symptom onset.

Misdiagnosis: Previous generations may not have received an accurate diagnosis.

Reduced penetrance: A carrier may never develop recognisable symptoms.

Incomplete family information: Relevant family history may be unavailable.

A negative family history does not automatically exclude a genetic cause.

How Does a Genetic Counsellor Investigate This?

A genetic counsellor usually collects a three-generation family history, including grandparents, parents, siblings, aunts, uncles and children.

The counsellor records the age of symptom onset, diagnosis, current age or age at death and any history of related neurological conditions.

A pedigree can help identify a possible autosomal dominant inheritance pattern and determine whether genetic testing should be considered.

5. Who Should Be Tested First in a Family?

When a family has a history of dementia, one of the most important questions is: Who should undergo genetic testing first?

The general recommendation is to test an affected family member first, whenever possible.

This approach is called proband-first testing or diagnostic testing of the affected individual.

Why Should an Affected Individual Be Tested First?

Imagine a family in which:

The mother developed dementia at 52.
Her sister developed dementia at 55.
Her brother is currently healthy.
Her daughter is 28 and worried about developing dementia.

The daughter wants to know whether she has inherited the condition.

However, testing the daughter directly without first establishing the genetic cause in her affected mother may not provide a clear answer.

Instead, the preferred approach is to perform genetic testing on the mother.

If a disease-causing variant is identified, the daughter can subsequently undergo targeted testing to determine whether she has inherited the same variant.

What Happens If a Pathogenic Variant Is Identified?

Suppose genetic testing identifies a pathogenic variant in the PSEN1 gene in the affected mother.

This establishes a molecular explanation for the familial Alzheimer’s disease.

Because PSEN1-related familial Alzheimer’s disease follows an autosomal dominant inheritance pattern, each biological child of the mother has a 50% chance of inheriting the variant.

The daughter can now choose to undergo predictive genetic testing after appropriate genetic counselling.

Possible outcomes include:

Positive result: The daughter carries the familial pathogenic variant. This indicates an increased likelihood of developing the associated condition, although the exact age of onset may not be predictable.

Negative result: The daughter does not carry the specific familial pathogenic variant. She is not at increased risk from that particular inherited variant.

Uncertain result: If the affected relative’s testing identifies a variant of uncertain significance (VUS), it cannot be used as a definitive predictive test for other relatives.

What If the Affected Individual Is Unavailable?

Sometimes the affected family member may have died, be unavailable for testing or be unable to provide a sample.

In such situations, testing another affected relative may be considered.

If no affected relative is available, testing an unaffected individual may sometimes be discussed based on the family history. However, the limitations of a negative result must be clearly explained.

A negative result in an unaffected person, when no familial pathogenic variant has previously been established, is generally considered an uninformative negative. It does not necessarily exclude a hereditary cause.

What Type of Genetic Testing May Be Considered?

Depending on the clinical presentation and suspected condition, testing may include:

Targeted single-gene testing.

Hereditary dementia gene panel.

C9orf72 repeat expansion testing.

Whole exome sequencing or whole genome sequencing in selected cases.

Importantly, standard sequencing panels may not reliably detect certain repeat expansions, such as the pathogenic hexanucleotide repeat expansion in C9orf72. A suitable specialised testing method may therefore be required.

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