Search Strategy for Genetic Movement Disorders

Overview

Making a precise genetic, molecular diagnosis provides substantial value to families, even if there is no disease-specific treatment. A specific genetic diagnosis can narrow the horizon of prognostic possibility and help families to identify and network with other similarly affected persons. It can also clarify risks and provide useful information for relatives of the affected individual.

Efficient use of online resources is essential for neurologists evaluating patients with possible genetic diagnoses. As discussed throughout this book, a careful history of present illness, three-generation family history, comprehensive neurological examination, and characterization of movement disorder phenomenology form the foundation of this process. Until recently, these clinical practices usually occurred prior to and guided decisions about cost-effective and medically appropriate tests. Increasingly, the diagnostic role of these good clinical practices is transitioning to posttest medical decision making, that is, from guiding decisions to order specific tests to interpreting results of already-completed nonhypothesis driven tests such as Whole Exome Sequencing. This is partly because costs and time for obtaining results from Next-Generation Sequencing have both decreased markedly, as is updated by the National Institutes of Health: https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost . These lower costs and higher availability mean primary physicians and others more commonly have ordered these tests prior to the first neurology consultation.

Scope of the Challenge for Integration of Genetics into Neurology Practice

Clinical experience now must be integrated with freely available datasets containing vast amounts of information. An efficient hub for pre- and postclinic workflow, which also demonstrates the magnitude of relevant information, is the database Online Mendelian Inheritance in Man (OMIM), available at http://www.omim.org /. OMIM is an online catalog of human genes and phenotypes. This resource is provided without a user-fee and is intended for use primarily by physicians, other professionals, and researchers concerned with genetics.

OMIM is updated multiple times per month, as shown at https://omim.org/statistics/updates . For example, on May 28, 2021 there were five new entries, including Developmental and Epileptic Encephalopathy 96 (MIM #619340), and two new clinical synopses, including Leukodystrophy, Hypomyelinating 22 (MIM #619328). There were also multiple updates: thirty entries, including Aromatic l -Amino Acid Decarboxylase Deficiency (MIM #608643), and one clinical synopsis, Neurodevelopmental Disorder with Dysmorphic Features, Spasticity, and Brain Abnormalities (MIM #615801).

Current OMIM entry totals can be found at http://omim.org/statistics/entry/ . For example, on May 28, 2021, there were 25,894 entries. These included 16,495 gene descriptions (autosomal 15,659, X-Linked 748, Y-Linked 51, and mitochondrial 37), an increase of 11% since 2015. There were 6089 entries with “phenotype description where the molecular basis is known” (5694 autosomal, 356 X-linked, 5 Y-linked, 34 mitochondrial), an overall increase of 39% since 2015. Each number serves as a link to that gene list, and lists can be downloaded by users and imported into programs like Excel ^R . There are also entries for “phenotype description or locus, molecular basis unknown” and for “phenotypes with suspected Mendelian basis.”

The complexity of the genotype/phenotype relationship can be appreciated from the current statistics on numbers of phenotypes per genotype: https://omim.org/statistics/geneMap . For example, as of May 28, 2021, there were 1351 genes with two or more established phenotypes.

OMIM http://www.omim.org/ can be used as a diagnostic search engine when faced with a difficult diagnosis. OMIM can be searched using any term or “phrase” in quotations, and multiple terms can be combined with “and,” “or,” “or not”. Helpful advice is provided on the main page including example searches and a link to a tutorial. Using a single movement disorder phenomenology as a search term generates hundreds of entries. Adding and “…” (i.e., another key feature) narrows the number of possibilities. It can be especially helpful to add findings which are outside of the nervous system to this list, for example, splenomegaly. For example, the search “ataxia” generates 930 clinical synopses. The search “ataxia and splenomegaly” generates 37 clinical synopses. Adding “and “vertical gaze palsy”” yields one clinical synopsis, for Niemann-Pick Type C1, as shown in Table B.1 .

To make OMIM a practical clinical tool, the next section, OMIM SEARCH EXAMPLES, applies search principles to three actual clinical cases. The point of the exercise is to use OMIM to generate a differential diagnosis in hopes of determining the molecular basis for the disease. There are many search options, but these searches will be simple and straightforward. Numbers in this section are from search conducted 5/28/2021.

OMIM Search Example