Phenotype–genotype complexities: opening DOORS
Authors: Samuel F Berkovic, Jozef Gecz
Journal: The Lancet Neurology (2013)

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.1Yang Y Muzny DM Reid JG et al.Clinical whole-exome sequencing for the diagnosis of mendelian disorders.N Engl J Med. 2013; 369: 1502-1511Crossref PubMed Scopus (1437) Google Scholar 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 colleagues2Campeau PM Kasperaviciute D Lu JT et al.The genetic basis of DOORS syndrome: an exome sequencing study.Lancet Neurol. 2013; (published online Nov 29.)http://dx.doi.org/10.1016/S1474-4422(13)70265-5PubMed Google Scholar show that, in about half of affected 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 five main features—deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures.3Cantwell RJ Congenital sensori-neural deafness associated with onycho-osteo dystrophy and mental retardation (D.O.O.R. syndrome).Humangenetik. 1975; 26: 261-265PubMed Google Scholar, 4Qazi QH Nangia BS Abnormal distal phalanges and nails, deafness, mental retardation, and seizure disorder: A new familial syndrome.J Pediat. 1984; 104: 391-394Summary Full Text PDF PubMed Scopus (19) Google Scholar Campeau and colleagues' findings2Campeau PM Kasperaviciute D Lu JT et al.The genetic basis of DOORS syndrome: an exome sequencing study.Lancet Neurol. 2013; (published online Nov 29.)http://dx.doi.org/10.1016/S1474-4422(13)70265-5PubMed Google Scholar draw attention to several important issues. First, with the widespread availability of whole-exome sequencing technology, novel findings, or discoveries, are now easier to come accross, even in small series or single case studies. Some of these findings might be false positives, but in Campeau and colleagues' report, robust inferences about the genetics of DOORS syndrome can be made because the investigators identified TBC1D24 mutations in a large proportion of affected 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,2Campeau PM Kasperaviciute D Lu JT et al.The genetic basis of DOORS syndrome: an exome sequencing study.Lancet Neurol. 2013; (published online Nov 29.)http://dx.doi.org/10.1016/S1474-4422(13)70265-5PubMed Google Scholar 18 families had individuals with all five 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 five 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 different mutations in a gene can have different clinical manifestations, provides a big challenge to understanding mechanisms and to the use of exome-sequence data in diagnosis and prognosis.5Cooper DN Krawczak M Polychronakos C Tyler-Smith C Kehrer-Sawatzki H Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease.Hum Genet. 2013; 132: 1077-1130Crossref PubMed Scopus (409) Google Scholar Recessive mutations of TBC1D24 not only affect 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,6Falace A Filipello F La Padula V et al.TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy.Am J Hum Genet. 2010; 87: 365-370Summary Full Text Full Text PDF PubMed Scopus (124) Google Scholar a more severe syndrome with focal epilepsy, cognitive impairment, and cerebro-cerebellar malformations,7Corbett MA Bahlo M Jolly L et al.A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.Am J Hum Genet. 2010; 87: 371-375Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 8Afawi Z Mandelstam S Korczyn AD et al.TBC1D24 mutation associated with focal epilepsy, cognitive impairment and a distinctive cerebro-cerebellar malformation.Epilepsy Res. 2013; 105 (24): 240Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar a severe infantile-onset myoclonic epilepsy with dementia, progressive cerebral atrophy and childhood death,9Guven A Tolun A TBC1D24 truncating mutation resulting in severe neurodegeneration.J Med Genet. 2013; 50: 199-202Crossref PubMed Scopus (31) Google Scholar and epilepsy in infancy with migrating focal seizures.10Milh M Falace A Villeneuve N et al.Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy.Hum Mutat. 2013; 34: 869-872Crossref PubMed Scopus (81) Google Scholar 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 KCNT1,11Barcia G Fleming MR Deligniere A et al.De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.Nat Genet. 2012; 44: 1255-1259Crossref PubMed Scopus (333) Google Scholar another example of genetic heterogeneity. The molecular function of TBC1D24 protein has begun to emerge over the past 4 years. Our group7Corbett MA Bahlo M Jolly L et al.A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.Am J Hum Genet. 2010; 87: 371-375Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar and Falace and colleagues,6Falace A Filipello F La Padula V et al.TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy.Am J Hum Genet. 2010; 87: 365-370Summary Full Text Full Text PDF PubMed Scopus (124) Google Scholar using different in-vitro assays, have shown that overexpression of TBC1D24 protein in primary mouse neurons directly affects neurite length and branching6Falace A Filipello F La Padula V et al.TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy.Am J Hum Genet. 2010; 87: 365-370Summary Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 7Corbett MA Bahlo M Jolly L et al.A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.Am J Hum Genet. 2010; 87: 371-375Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar as well as axonal arborisation and specification.7Corbett MA Bahlo M Jolly L et al.A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.Am J Hum Genet. 2010; 87: 371-375Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar TBC1D24 interacts with Arf6, one of a Ras-related family of small GTPases,6Falace A Filipello F La Padula V et al.TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy.Am J Hum Genet. 2010; 87: 365-370Summary Full Text Full Text PDF PubMed Scopus (124) Google Scholar which, among other functions, is involved in the regulation of exocytosis and endocytosis dynamics and neuronal cell polarity,12Schweitzer JK Sedgwick AE D'Souza-Schorey C ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis.Semin Cell Dev Biol. 2011; 22: 39-47Crossref PubMed Scopus (103) Google Scholar providing an attractive molecular mechanism for the seizures and intellectual disability seen in most TBC1D24-associated phenotypes, including DOORS. Campeau and colleagues2Campeau PM Kasperaviciute D Lu JT et al.The genetic basis of DOORS syndrome: an exome sequencing study.Lancet Neurol. 2013; (published online Nov 29.)http://dx.doi.org/10.1016/S1474-4422(13)70265-5PubMed Google Scholar also show that the crucial function of TBC1D24 extends beyond neuronal cells, to chondrocytes and bone. Why only some TBC1D24 mutations are associated with a chondrocyte and bone phenotype is unknown. The underlying cellular and molecular mechanism for the growing number of TBC1D24-associated phenotypes is far from clear. Whether the explanation is in the TBC1D24 mutations themselves, TBC1D24-associated proteins and pathways, or precise timing of TBC1D24 function during development has not been established. The framework for understanding phenotype–genotype correlation is more complicated than was envisaged by Garrod and his early successors. Elucidation of this association will be crucial for deeper understanding in the laboratory and the clinic, and for the development of new treatments. In view of what is known so far about TBC1D24-mutation pleiotropy, studies such as that of Campeau and colleagues2Campeau PM Kasperaviciute D Lu JT et al.The genetic basis of DOORS syndrome: an exome sequencing study.Lancet Neurol. 2013; (published online Nov 29.)http://dx.doi.org/10.1016/S1474-4422(13)70265-5PubMed Google Scholar will provide new opportunities toward achieving this goal. We declare that we have no conflicts of interest. The genetic basis of DOORS syndrome: an exome-sequencing studyOur findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. Full-Text PDF Open Access