In LCA: Naming Versus Numbering
Gene mutations in the rare inherited retinal disease of Leber congenital amaurosis commonly are referred to by their gene name, such as GUCY2D, RPE65 and CEP290. But sometimes, as LCA patients and families have discovered, they are referenced numerically as LCA1, LCA2 and LCA10, respectively.
Why the difference? It’s confusing.
LCA1 through LCA18 exist in a continually updated online catalog of human genes and genetic disorders called Online Mendelian Inheritance in Man. Mendelian inheritance is based on the ideas of Gregor Johann Mendel, a 19th-century Moravian monk known as the father of modern genetics.
One source of confusion for LCA families is that there are 27 genes that can cause LCA, but only LCA1 through LCA18 are cataloged. For most genes, OMIM includes only selected mutations based on criteria such as the first mutation discovered, high-population frequency, distinctive phenotype and more. LCA families with genes not included in the database are left to wonder why they’ve been left out.
OMIM focuses on the molecular relationship between genetic variation and phenotypic expression and is considered a phenotypic companion to the Human Genome Project, which funds the database. The HGP international research effort from 1990 to 2003 culminated in a blueprint for building a person by completing an entire sequence of the human genome.
OMIM is a continuation of Dr. Victor A. McKusick’s Mendelian Inheritance in Man published through 1998. Created in 1985 through a collaboration between the National Library of Medicine and the William H. Welch Medical Library at Johns Hopkins University School of Medicine, OMIM went online in 1987.
For example, OMIM refers to GUCY2D as LCA1, #204000 (phenotype MIM number), located at 17p13.1 with a gene/locus MIM number of 600179.
“A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-1 (LCA1) is caused by a homozygous mutation in the gene encoding retinal guanylate cyclase (GUCY2D: 600179) on chromosome 17p13.”
There’s more, but that can be left to physicians, genetics’ professionals, researchers and students studying advanced science and medicine.
“For a patient with LCA or their family, what’s important is not the LCA## symbol, but, rather, a) the underlying affected gene; b) whether inheritance is dominant or recessive (dominant is rare); and c) the specific mutation or mutations,” according to Stephen P. Daiger, PhD, Professor in Environmental and Genetic Sciences at the University of Texas Health Science Center and director of the Laboratory for Molecular Diagnosis of Inherited Eye Diseases.
“This is the information which decides, for example, whether someone is eligible for a clinical trail focused on a specific gene, e.g., LUXTURNA™ for RPE65,” he said. “It is very important to know and remember this information.”