Phenotype–genotype complexities: opening DOORS

The escalating pace of molecular genetic discoveries in neurological diseases is repeatedly providing surprises that challenge our ability to match phenotype and genotype. With the current transition of whole-exome sequencing from the laboratory to clinical use, the ability to understand and interpret molecular-level data becomes ever more important. The classic view of one gene encoding one protein, with disruption resulting in one disease, is rooted in Archibald Garrod’s remarkable insights into inborn errors of metabolism more than 100 years ago. This simplistic view now seems to be in doubt for many genes. In The Lancet Neurology, Philippe Campeau and colleagues show that, in about half of aff ected people from the 26 families studied, DOORS syndrome is due to a mutation in the gene TBC1D24. DOORS, a rare autosomal recessive disorder, gets its name from an acronym of its fi ve main features—deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures. Campeau and colleagues’ fi ndings draw attention to several important issues. First, with the widespread availability of whole-exome sequencing technology, novel fi ndings, or discoveries, are now easier to come accross, even in small series or single case studies. Some of these fi ndings might be false positives, but in Campeau and colleagues’ report, robust inferences about the genetics of DOORS syndrome can be made because the investigators identifi ed TBC1D24 mutations in a large proportion of aff ected individuals in a unique, large international cohort of patients with this rare disorder. Second, even rare, distinctive, and multisystem disorders can be genetically heterogeneous. In Campeau and colleagues’ study, 18 families had individuals with all fi ve main features of DOORS—in only nine of these families was the TBC1D24 mutation detected, leaving 17 families (including the eight who had an individual with fewer than fi ve features) with the cause for their DOORS undetermined. Genetic heterogeneity is emerging as the rule in many neurological disorders that seem otherwise clinically homogeneous. Third, pleiotropy, in which the same or diff erent mutations in a gene can have diff erent clinical manifestations, provides a big challenge to under standing mechanisms and to the use of exome-sequence data in diagnosis and prognosis. Recessive mutations of TBC1D24 not only aff ect normal development of nails, bone, and brain in DOORS syndrome, but also cause a large array of other neurological phenotypes. These phenotypes include mild infantile-onset myoclonic epilepsy with normal intellect and neuroimaging, a more severe syndrome with focal epilepsy, cognitive impairment, and cerebro-cerebellar malformations, a severe infantile-onset myoclonic epilepsy with dementia, progressive cerebral atrophy and childhood death, and epilepsy in infancy with migrating focal seizures. In these other TBC1D24-associated syndromes, the investigators did not detect deafness or bone or nail abnormalities. Epilepsy in infancy with migrating focal seizures is more often due to mutation of the potassium channel gene KCNT1, another example of genetic heterogeneity. The molecular function of TBC1D24 protein has begun to emerge over the past 4 years. Our group and Falace and colleagues, using diff erent in-vitro assays, have shown that overexpression of TBC1D24 protein in primary mouse neurons directly aff ects neurite length and branching as well as axonal arborisation and specifi cation. TBC1D24 interacts with Arf6, one of a Ras-related family of small GTPases, which, among other functions, is involved in the regulation of exocytosis and endocytosis dynamics and neuronal cell polarity, providing an attractive molecular mechanism for the seizures and intellectual disability seen in most Published Online November 29, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70237-0