Finding the mutations that cause genetic disorders by studying genes and their modes of inheritance
How are mutations for genetic disorders found? There are long and complicated processes to identify the cause of genetic disorders. Three processes discussed in this paper are identifying mutation types, studying the mode of inheritance of genes, and describing universal phenotypic symptoms of genetic disorders for diagnosis.
Figure 1- Mutations that cause Kabuki Syndrome
Source: Hannibal, MC, et al. Am J Med Genet A. 2011
Not all mutations are alike. A type of mutation called silence mutation codes for the same protein as the normal gene sequence would code for. There would be no consequences for the individual. However, many severe genetic disorders are caused by Loss of Function (LoF) variants (Lyon 2012). LoF variants interfere with protein function by not coding for a protein or decreasing the function of a protein (Lyon 2012). They include nonsense mutations, in which one base is replaced with another, forming a stop codon so a protein does not get built completely. The incomplete protein may not function at all or only partly function. LoF variants also include insertions and deletions, in which a base is inserted or deleted, causing the wrong amino acids to form, and consequently, the wrong or nonfunctional proteins (Lyon 2012). Kabuki syndrome is a genetic disorder caused by several nonsense mutations, as shown in Figure 1 (Hannibal 2011). However, other types of mutations cause genetic disorders too. For example, a missense mutation, in which one base is replaced with another so a different amino acid is used, is the cause of Ogden syndrome (Lyon 2012). Identifying the type of mutation is crucial to understanding how the mutation occurred.
The mode of inheritance of genes is usually studied by using Mendel’s principles of dominance and recessive genes. In fact, many genetic disorders can be classified using these terms (Lyon 2012). However, not all genes have clear dominance or recessive traits; some genes are neither in complex diseases (Lyon 2012). Family histories of diseases are useful to study to understand how these diseases are inherited and where a mutation happened. Studying families is especially useful to study rare diseases or new mutations that have not been affected by natural selection yet (Lyon 2012).
To diagnose a genetic disorder, a patient must exhibit phenotypic symptoms related to the disorder. However, it is difficult to accurately know phenotypic symptoms because genes are expressed differently in individuals (Lyon 2012). Administering tests to study genomic information and standardizing vocabulary used to describe symptoms can allow doctors and physicians to compare symptoms and diagnose with more certainty. It is crucial to develop standardized medical terms for symptoms so there are lots of efforts being made, such as projects like the Unified Medical Language System (Pathak 2011). The Human Phenotype Ontology serves to standardize abnormal symptoms (Robinson 2008). Efforts for diagnosing psychiatric disorders are also being made. Research Domain Criteria proposed using neurobiological measures and observable behavior dimensions to classify psychopathology (Lyon 2012).
Causes of some genetic disorders have been identified. However, some of them may be “false positives” (Lyon 2012). Some of the causes of genetic disorders may not actually be causes although they are apparent in the genes of some patients. False positives include genes that are found in low frequencies in healthy populations (Lyon 2012). Some recorded causes of sporadic dilated cardiomyopathy were found to be false positives when the National Heart, Lung, and Blood Institute-Exome Sequencing Project calculated their allele frequencies (Norton 2012).
Researchers and doctors need to keep in mind that there some genes that seem likely to be the causes of genetic disorders may in reality not be.
Learning about genes, how they are inherited, and the symptoms that are caused by mutations are crucial in figuring out what the causes of genetic disorders are.
Works Cited
Hannibal MC, et al: Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet A. 2011, 155A: 1511-1516.
Lyon GJ, Wang K: Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress. Genome Medicine. 2012, 4: 58. 10.1186/gm359.
Norton N, Robertson PD, Rieder MJ, Zuchner S, Rampersaud E, Martin E, Li D, Nickerson DA, Hershberger RE: Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ Cardiovasc Genet. 2012, 5: 167-174. 10.1161/CIRCGENETICS.111.961805.
Pathak J, Wang J, Kashyap S, Basford M, Li R, Masys DR, Chute CG: Mapping clinical phenotype data elements to standardized metadata repositories and controlled terminologies: the eMERGE Network experience. J Am Med Inform Assoc. 2011, 18: 376-386. 10.1136/amiajnl-2010-000061.
Robinson PN, Kohler S, Bauer S, Seelow D, Horn D, Mundlos S: The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet. 2008, 83: 610-615. 10.1016/j.ajhg.2008.09.017.
