**4. Real-life case**

## **4.1 Variation in the frizzled class receptor 6 (FZD6) protein found in individuals with the nail disorder**

Nonsyndromic congenital nail disorder 1 (OMIM #1161050) is a condition affecting the fingernails and toenails characterized by extremely thick nails, onycholysis, hyponychia and claw-like appearance. Autosomal recessive mutations in the FZD6 gene (OMIM \*603409) were found to be associated with this disorder [110]. FZD6 is a member of the highly conserved WNT receptors family crucial for developmental processes and differentiation. The study conducted on mice demonstrated that FZD6-mediated Wnt signaling has a regulatory role in the differentiation process of claw/nail formation [111].

In a previous study from our group, a Turkish family with three affected individuals reported. After performing WES on the index case, 96 de novo heterozygous, 421 homozygous, and 185 compound heterozygous variants were obtained

from data analysis. Employing population MAF frequency filtering according to the mode of inheritance has decreased the number of variants to 19, 46, 3 for de novo heterozygous, homozygous, compound heterozygous variants respectively. Further prioritization approaches were applied by integrating pathogenicity prediction scores provided by PrimateAI and other tools, model organism phenotypes, and gene intolerance scores. Ultimately, the FZD6 gene was found to be the most prominent gene even though the gene does not have a high intolerance score. However, the potential functional impact of the mutation was supported by the examination of the evolutionary conservation of the disturbed amino acid region. The region was found to be evolutionarily conserved in other FZD6 orthologues including *Pan troglodytes*, *Macaca mulatta*, *Pongo abelii*, *Bos taurus*, *Canis lupus familiaris*, *Rattus norvegicus*, *Mus musculus*, *Xenopus laevis*. The index case had a homozygous 8 bp deletion on the FZD6 gene caused p.Gly559Aspfs\*16. Additionally, this mutation has previously been reported in two other Turkish families. It is also reported that all three families have a common ancestor. In this study, the pathogenicity mechanism for this mutation in nail dysplasia is provided for the first time. The mutation causes a frameshift and creates a premature stop codon at position 16 of the new reading frame [112].

This case study demonstrated that the promising applications of evolutionary approaches assist the clinical diagnosis.

## **5. Conclusion**

Associating genomic variants with diseases is a multistep process. The early steps of this process are highly automated through the usage of several bioinformatics tools. However, the final prioritization step, which is the most critical step, is not completely automated. It requires a comprehensive interpretation together with integrative approaches. In this chapter, we aimed to explain the potential of integrating evolutionary principles into variant prioritization toward clinical utility. This chapter provides sufficient basic information to understand the required bioinformatics tools, various databases with increasing sequence data from individuals as well as model organism research. Finally, we conclude that the pre-evaluation of individual variations with evolutionary approaches can help shorten the diagnostic odyssey, hence saving time and resources. This chapter aims to contribute to the integration of evolutionary genetics to medical genomics. Further studies that combine theoretical and analytical approaches are needed to improve the field of precision medicine via the use of evolutionary insight.

**143**

**Author details**

Ugur Sezerman\*, Tugce Bozkurt and Fatma Sadife Isleyen

\*Address all correspondence to: sezermanu@gmail.com

provided the original work is properly cited.

Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

Graduate School of Health Sciences, Biostatistics and Bioinformatics Program,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Integrating Evolutionary Genetics to Medical Genomics: Evolutionary Approaches to Investigate…*

*DOI: http://dx.doi.org/10.5772/intechopen.92738*

### **Conflict of interest**

The authors declare no conflict of interest.

*Integrating Evolutionary Genetics to Medical Genomics: Evolutionary Approaches to Investigate… DOI: http://dx.doi.org/10.5772/intechopen.92738*
