Critique the paper "Nail-Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity" by considering the questions provided and placing your answers in the context of the Ghoumid et al work in order to demonstrate an understanding of the paper and more general material covered in the Introductory module. Please remember that although the questions are numbered, your assignment should be in essay format.

1. Nail-patella syndrome demonstrates a range of clinical phenotypes; what explanations are there for this phenomenon?

2. LMX1B encodes a LIM-domain containing transcription factor. What is a transcription factor and how can mutations within a gene affect the biological activity of the protein?

3. The authors mention that the homeodomain is "highly conserved"; what does this mean and what is the relevance of this statement?

4. A number of different types of pathogenic mechanisms are mentioned - haploinsufficiency, dominant negative and gain of function. Describe what is meant by these different terms and discuss the relevance to phenotype.

5. Some information about the patients is provided but do you think that the information provided is relevant and sufficient? Is there anything more you would like to know and why?

6. According to Ensembl (www.ensembl.org) there are four protein coding transcripts for LMX1B. Ghoumid et al based their analyses on one of these (NM_002316). Do you see any problems with this; if so, why and what?

7. The study applied four molecular analysis techniques - why?

8. Briefly describe how Sanger sequencing is performed.

9. Why did the research team perform genomic sequencing of all of LMX1B? How can mutations in non-coding regions lead to a functional effect?

10. The researchers describe a number of "filters" that they applied when looking at the genomic sequence data for LMX1B. Explain why those filters were applied giving your opinion as to whether they are appropriate filters or whether others should have been applied (giving reasons).

11. The authors mention using in silico prediction tools, Polyphen2 and SIFT. Why are these tools used and how reliable do you think the prediction is? Do you think there is a need for any further evidence when studying pathogenicity?

12. Explain why mutations cluster in two domains?

13. The authors state that based on Supplementary Figure 2 there was "no linkage [with disease] to LMX1B locus". What is the evidence for this statement?

14. Provide any final thoughts on the scientific validity and importance of this study.

Discuss the Ghoumid et al paper using the following questions to prompt your thinking. You need to state what the aims of their study were, their results and conclusions. Do you think their conclusions are valid? Do you think they took the right methodological approach and, if not, what would have been an alternative approach.

Remember, this should be in essay style, don't answer the questions in a numerical fashion.

The essay should be 1500-2500 words and you will be marked on structure and quality of academic writing as well as scientific writing. (refrences are not included in the work count)

You are not commenting on the quality of writing of the paper.

Article - Nail-Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795216/