goldstein:%0A(4%20points)%20You%20are%20a%20clinician%20scientist%20(MD/PhD)%20in%20the%20neurology%20department,%20and%20you%20have%20two%20patients%20visit%20your%20clinic%20that%20are%20identical%20twins.%20They%20have%20the%20exact%20same%20neurological%20symptoms,%20but%20those%20symptoms%20don't%20fit%20any%20profiles%20for%20known%20disorders.%20Because%20they%20are%20identical%20twins,%20you%20hypothesize%20that%20a%20genetic%20mutation%20is%20causing%20their%20symptoms.%20What%20approach%20would%20you%20take%20to%20try%20and%20track%20down%20their%20genetic%20mutation(s),%20and%20why?%0A-

Answer 1

To investigate the potential genetic mutations causing the identical twin patients' neurological symptoms, I would recommend a multi-step approach focused on whole-exome sequencing (WES) or whole-genome sequencing (WGS). Here’s a breakdown of the steps involved and the rationale for this approach:

1. Clinical Assessment: First, I would conduct a thorough clinical evaluation to document the neurological symptoms in detail and gather comprehensive medical histories for both twins. This would provide context for the genetic findings.

2. Blood Sample Collection: I would obtain blood samples from both twins to extract DNA. Since they are identical twins, their genomes are nearly identical, which helps streamline the search for potential pathogenic mutations.

3. Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS):

   • WES focuses specifically on the coding regions of the genome, which is where many disease-causing mutations are found, and it is more cost-effective compared to WGS.
   • WGS covers the entire genome, including non-coding regions, which may also hold significant genetic information that could contribute to phenotypic expression. I would choose WGS if the financial and logistical resources are available since it provides a more comprehensive exploration of potential mutations, including those that might affect regulatory elements.

4. Data Analysis: After sequencing, I would employ bioinformatics tools designed to filter and analyze the data. Key points would include:

   • Comparing variants found in the twins' DNA to public databases (e.g., gnomAD, dbSNP) to identify novel mutations or rare variants.
   • Focusing on variants that are present in both twins but absent in the reference population, particularly those that affect protein function.
   • Considering mutations in known genes related to neurological disorders, even if the symptoms do not match known profiles.

5. Functional Studies (if necessary): If potentially pathogenic mutations are identified, I would consider conducting functional studies in relevant models (e.g., cell lines, animal models) to validate the impact of these mutations on neuronal function and pathology.

6. Family History and Additional Testing: It would also be helpful to investigate if other family members exhibit similar symptoms or if there is any family history of neurological disorders. Additionally, I could consider using technologies like RNA sequencing to look for expression differences.

7. Interpretation and Feedback: Once all data is analyzed and potential mutations are identified, I would consult with genetic experts and potentially discuss findings with the twins and their family, considering ethical implications and further clinical management based on the genetic findings.

The rationale behind using WES or WGS is that genetic mutations are common causes of unexplained neurological symptoms, especially when considering the identical nature of the twins. By understanding any genetic differences present between the twins, we may be able to pinpoint the underlying cause of their symptoms and potentially guide future treatment or management strategies.