Question

You are a clinician scientist (MD/PhD) in the neurology department, and you have two patients visit your clinic that are identical twins. They have the exact same neurological symptoms, but those symptoms don't fit any profiles for known disorders. Because they are identical twins, you hypothesize that a genetic mutation is causing their symptoms. What approach would you take to try and track down their genetic mutation(s), and why?

Answer 1

As a clinician scientist in neurology faced with two identical twins presenting with unexplained neurological symptoms, a systematic approach to identify potential genetic mutations would be essential. Here's the step-by-step approach I would take:

### 1. Detailed Clinical Evaluation
- **History and Symptoms**: Gather thorough medical histories and conduct comprehensive neurological examinations. Documenting the onset, progression, and specific features of their symptoms could provide clues for potential genetic syndromes or pathways involved.

### 2. Family Pedigree Analysis
- **Family History**: Construct a family pedigree focusing on the occurrence of similar symptoms in other family members or known genetic disorders. This could provide insights into the inheritance pattern.

### 3. Genetic Testing
- **Targeted Gene Panel**: Initiate testing using a targeted gene panel specifically for neurological disorders. This approach can efficiently identify known mutations associated with their neurological symptoms.

- **Whole Exome Sequencing (WES)**: If targeted panels are inconclusive, I would recommend whole exome sequencing. WES sequences all coding regions of the genome and is a valuable tool for identifying novel or rare mutations that may not be part of standard panels.

- **Whole Genome Sequencing (WGS)**: If WES still does not yield results, consider WGS, which provides the most comprehensive view of the genome, capturing non-coding regions and structural variants that might play a role in the disease.

### 4. Functional Studies
- **In vitro & Animal Models**: If candidate mutations are identified, I would propose functional studies using cell cultures or animal models to assess the impact of these mutations on neuronal function and related pathways.

### 5. Collaborate with Geneticists & Bioinformaticians
- **Multidisciplinary Team**: Collaborate with geneticists to interpret complex data and with bioinformaticians to analyze sequencing results, looking for variants that are potentially pathogenic.

### 6. Evaluate the Role of Environment
- **Environmental & Lifestyle Factors**: Since identical twins share genetics, assess environmental factors that might contribute to the expression of these symptoms. This involves reviewing their living conditions, exposures, and lifestyle habits.

### 7. Longitudinal Monitoring
- **Follow-Up Testing and Monitoring**: Given that neurological conditions can change over time, consider monitoring the patients longitudinally for new symptoms or progression of existing symptoms, which could provide additional diagnostic clues.

### Rationale
The approach outlined provides a scalable strategy starting from a focused clinical evaluation to extensive genetic analyses. Identical twins increase the likelihood of a shared genetic factor, making genetic screenings particularly relevant. WES and WGS can help capture both common and rare mutations relevant to their symptoms, thus advancing our understanding of potential novel pathways that might be involved in their condition. This methodical approach combines clinical insight with cutting-edge genomic technologies to enhance the probability of identifying the underlying genetic cause of the twins' neurological symptoms.