The multiple faces of TOR1A: different inheritance, different phenotype.

Flipping through the pages of any textbook of genetics, the reader would soon come across the seminal distinction between ‘simple’ Mendelian (or monogenic) disorders, caused by specific defects in a single gene, and ‘complex’ multifactorial disorders, which arise from the combination of many genetic and environmental factors. Monogenic disorders are further subdivided into dominant or recessive, depending on whether only one copy or both copies of the gene need to be mutated in order for the disease to manifest. Yet, this simple paradigm ‘gene mutation phenotype’ has been challenged in recent years, and it is now obvious that monogenic diseases are much more complex than previously thought. For instance, most dominant disorders are characterized by variable expressivity and incomplete penetrance: individuals who carry the same genetic mutation may either develop a full-blown clinical phenotype, present milder manifestations of the disease, or even remain completely asymptomatic. The mechanisms underlying these phenomena are largely unknown, although the presence of genetic modifiers in the same or in distinct genes has been advocated in some cases. The advent of next-generation sequencing techniques has further highlighted the complexity of monogenic disorders, often expanding the phenotypic spectrum associated with variation in a single gene to encompass distinct conditions. But even more challenging to the principles of Mendelian genetics is the observation that mutations in the same gene may behave either in a dominant or a recessive way in distinct pedigrees. In this issue of Brain, Kariminejad and co-workers provide one such example, by revealing that individuals who are homozygotes for mutations in TOR1A display a genetic disorder which is clearly different from that observed in heterozygous carriers (Kariminejad et al., 2017). TOR1A, encoding the protein TorsinA, was the first gene to be associated with isolated early-onset dystonia (termed DYT1-dystonia). In all affected individuals, the causative mutation was found to be a heterozygous 3 bp GAG deletion in exon 5, resulting in the loss of one of a pair of glutamic acid residues towards the C-terminus of the protein (p.Glu303del). A few other heterozygous variants have been reported in dystonic patients, but their pathogenic significance remains to be established. DYT1-dystonia is an autosomal dominant disorder with variable expressivity and incomplete penetrance: more than 70% of individuals carrying the GAG deletion remain asymptomatic throughout their lives, while 20–30% of mutation carriers manifest the dystonic phenotype, which is usually severe and generalized but can also remain focal or segmental in a minority of patients (Ozelius and Lubarr, 1993). By using a whole exome sequencing approach, Kariminejad and colleagues identified homozygous pathogenic variants of TOR1A (including the same p.Glu303del variant and a novel p.Gly318Ser missense variant) in four children from three unrelated consanguineous families presenting an overall different and more severe disorder, characterized by congenital contractures of multiple joints, dysmorphic features, severe psychomotor delay, increased muscle tone, and limb tremor. At their most recent examination, between 2 and 4 years of age, all children had developed strabismus, moderate to severe intellectual disability and progressive microsomia. Interestingly, both tremor and contractures seemed to improve over time (with tremor disappearing by age 18 months in two siblings), while strabismus was reported to worsen. None of the affected children had any obvious sign of dystonia, but two of them developed stereotypic hand movements, facial grimacing and neck extension movements, which could possibly be dystonic in nature (Kariminejad et al., 2017). TOR1A is only the latest example of an expanding group of genes in which mutations can be found either on one or both alleles. In true dominant disorders, pathogenic variants BRAIN 2017: 140; 2764–2775 | 2764