Modifier genes in Mendelian disorders: the example of cystic fibrosis

• Published in: Annals of the New York Academy of Sciences Vol. 1214; no. 1; pp. 57 - 69
• Main Author: Cutting, Garry R.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01-12-2010; Wiley Subscription Services, Inc
• Subjects: Alleles; candidate gene; Cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - physiopathology; Cystic Fibrosis - therapy; Disease; Genes; genome wide; Genome-Wide Association Study; heritability; Humans; Multifactorial Inheritance - genetics; variation
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2010.05879.x

In the past three decades, scientists have had immense success in identifying genes and their variants that contribute to an array of diseases. While the identification of such genetic variants has informed our knowledge of the etiologic bases of diseases, there continues to be a substantial gap in our understanding of the factors that modify disease severity. Monogenic diseases provide an opportunity to identify modifiers as they have uniform etiology, detailed phenotyping of affected individuals, and familial clustering. Cystic fibrosis (CF) is among the more common life‐shortening recessive disorders that displays wide variability in clinical features and survival. Considerable progress has been made in elucidating the contribution of genetic and nongenetic factors to CF. Allelic variation in CFTR, the gene responsible for CF, correlates with some aspects of the disease. However, lung function, neonatal intestinal obstruction, diabetes, and anthropometry display strong genetic control independent of CFTR, and candidate gene studies have revealed genetic modifiers underlying these traits. The application of genome‐wide techniques holds great promise for the identification of novel genetic variants responsible for the heritable features and complications of CF. Since the genetic modifiers are known to alter the course of disease, their protein products become immediate targets for therapeutic intervention.