Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force – An Update

In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion‐based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease‐causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging‐based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

A BS TRACT: In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterionbased list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task  Originally, locus symbols (eg, DYT1) were used to specify chromosomal regions that had been linked to a familial disorder or a specific phenotype with an as yet unknown gene. 1 These symbols were systematically assigned in a numerical order (eg, PARK1, PARK2, etc.) and were regularly used by clinicians and researchers in lieu of the name for the condition (eg, DYT1 dystonia), even when the disease-causing gene (eg, TOR1A for DYT1) had been identified. This system has a number of weaknesses, making it unsuitable to use as a reference. 2,3 Therefore, the International Parkinson and Movement Disorder Society (MDS) initiated the Task Force for the Nomenclature of Genetic Movement Disorders to fix this "broken system." Thus, new recommendations and lists of monogenic movement disorders based on these recommendations were published in 2016. 3 Since then, both our knowledge and techniques of gene discovery have evolved enormously. Nextgeneration sequencing techniques have found their way into clinical and research settings, resulting in a large number of newly identified (potentially) diseasecausing genes and genetic variants reported in the literature. The interpretation of these genes and novel gene variants, particularly their pathogenicity, remains challenging. Some newly identified genes are just reported in a few individuals or small families, and sometimes the same variants are also found in controls and healthy family members, albeit at a lower frequency, whereas large families with convincing segregation are often missing. Further, reduced penetrance and phenocopies are used to explain imperfect segregation. Another challenge relates to the distinction between variants that are diseasecausing versus variants that confer an increased risk, as the boundaries are often blurred. Unconfirmed genes may be rapidly included in multigene panels for a given phenotype, which carries a risk of diagnostic results that are often difficult to interpret. Thus, a systematic approach to critically evaluate newly reported genes and updated lists of monogenic movement disorders based on our standardized criteria appear warranted.
The MDS Task Force for the Nomenclature of Genetic Movement Disorders and its Mandate When the MDS Task Force first convened, its initial mandate was to revise the naming system of genetic movement disorders. For this, a team of clinical neurologists and genetic experts from the field of movement disorders, supported by additional input from journal editors, medical experts from fields with already existing naming systems, representatives from GeneReviews, and the MDS membership developed rules for a new naming system and created lists for single-gene disorders known to cause several movement disorder phenotypes. This article expands these previously created lists and improves the naming system further. To achieve this, the newly published literature was systemically screened and curated. The recommendations were applied to newly reported gene-disease associations, carefully evaluated, and extensively discussed among the Task Force members and external experts when needed. Eventually, genes with convincing evidence were added by consensus to the respective phenotype lists. Genes that have yet to be confirmed are listed in the Supplementary tables.

Rules and Recommendations for the Nomenclature of Genetic Movement Disorders
Recommendations of the MDS Task Force for the revised naming system of genetic movement disorders have been described previously. 3 Briefly: (1) The list only includes disorders for which a causative gene has been identified. (2) Genes will be assigned a movement disorder prefix if the phenotype (eg, parkinsonism for PARK) is a prominent feature of the disease linked to pathogenic variants (also referred to as mutations) in that gene in the majority of cases. If two different movement disorders generally coexist with equal prominence or if a gene causes two different movement disorder phenotypes not necessarily coexisting but both as a prominent feature in about half of the patients, a double prefix should be assigned (eg, DYT/PARK-ATP1A3). If an additional movement disorder is present but less prevalent, no additional prefix is assigned but a cross reference is made between lists. (3) In addition to the phenotype-driven prefix, the naming system for each listed genetic disorder requires the name of the mutated gene (eg, DYT-TOR1A for dystonia caused by mutations in the TOR1A gene. (4) A prefix will only be assigned to disease-causing genes (as in monogenic disorders) and not to genetic risk factors. (5) Before including a gene in the list and assigning a prefix, a certain level of evidence for a genotype-phenotype association must be met (for details see Methods section).
What's New?
In this update, we focused on the three areas outlined below (1) We updated the previously published 3-5 lists of monogenic movement disorders. Through an extensive literature search, newly discovered disease-causing genes were identified and added for all movement disorder phenotypes covered by this Task Force. We identified 6 genes for parkinsonism (Table 1), 21 for dystonia  (Table 2), 38 for dominant and recessive ataxia (Table 3), 5 for chorea (Table 4), 7 for myoclonus (Table 5), 13 for spastic paraplegia (Table 6), 3 for paroxysmal movement disorders (Table 7), and 6 for mixed movement disorder phenotypes ( Table 8). As stated earlier, whenever a gene caused two different types of movement disorders with similar prevalence, a double prefix was assigned. When, however, a gene caused more than two different movement disorders and it was impossible to identify a consistent "core phenotype", we placed this gene in the newly added group of Mixed Movement Disorders (MxMD).
(2) Even after applying the previously developed criteria, 3 evaluating the evidence to support a causal gene-disease association was challenging, particularly for a more common disorder such as Parkinson's disease (PD). We thus piloted the application of an evidence-based framework developed by the Clinical Genome Resource (ClinGen) 6,7 to evaluate gene-disease associations using PD as an example (for details refer to the Methods section).
(3) Our initial set of recommendations assigned the prefixes NBIA for Neurodegeneration with Brain Iron Accumulation (NBIA) and PFBC for Primary Familial Brain Calcifications (PFBC) to genes linked to a movement disorder phenotype and characteristic imaging findings (evidence of brain iron accumulation for NBIA and cerebral calcification for PFBC). With this update, we decided to classify genes and phenotypes exclusively based on their clinical presentation and avoid the use of ancillary tests, such as imaging findings. This led to the reclassification of the genes previously assigned an NBIA or PFBC according to their predominant movement disorder phenotype. Nonetheless, since we acknowledge that imaging can be a distinguishing factor for these entities, we have added the suffix NBIA or PFBC and highlighted the imaging findings in the clinical features column where appropriate (eg, DYT-PANK2-(NBIA), PARK-SLC20A2-(PFBC)).

Literature Search
We performed a systematic literature search using standardized search terms (Table S1) and the National Center for Biotechnology Information's PubMed database (https://www.ncbi.nlm.nih.gov/pubmed). We searched for articles published until August 31, 2020 that reported patients with different movement disorders carrying genetic variants in newly identified and potentially disease-causing genes. We also evaluated relevant papers cited in the included articles. All listed articles were screened stepwise by title, abstract, and full text. All articles reporting at least one patient with a movement disorder carrying a potentially pathogenic variant in a newly identified gene were evaluated in detail. Another brief literature search focusing on unconfirmed candidate genes was conducted in May 2021 (search term: "[name of the gene] AND [disease in question]") and again in September 2021 in order to update previously curated lists.

Data Collection Process
We collected information on the number of affected and unaffected mutation carriers for each identified gene. For affected individuals, we further extracted data on the predominant phenotype as well as associated movement disorders or other non-movement disorder features. To evaluate the pathogenicity of variants in a gene, we additionally collected evidence for segregation, as well as additional molecular and functional evidence (see later).

Evaluation of Pathogenicity and Gene-Disease Association
To evaluate the involvement of a gene in causing a movement disorder, we assessed the previously described criteria 3 : (1) the presence of variants within one gene in multiple, unrelated affected individuals, reported by at least two independent groups; (2) evidence for segregation or a statistical association of the gene with disease proven by gene-wide burden analysis; and (3) variants with an in silico prediction to alter the normal biochemical effect of a gene product, further supported by functional evidence in human tissue, well-established cellular or animal models, or other biochemical or histological abnormalities. Once this information was extracted, all available data were discussed and evaluated by Task In addition to pathogenic variants as monogenic causes of the disease, some of the reported variants in CHCHD2 represent genetic risk factors also occurring in a considerable but lower number of control individuals when compared to PD patients. b These genes were previously included in the list of primary familial brain calcification.  Force members. In the few cases where uncertainty remained, external experts were consulted.
Recently, an evidence-based framework for evaluating gene-disease associations has been developed by the United States' National Institutes of Healthsupported ClinGen program. 6,7 We decided to employ these previously published criteria to evaluate ambiguous, newly reported PD genes, since here interpreting the pathogenicity was particularly challenging due to the frequently observed reduced penetrance 8,9 and high rate of phenocopies (5%). 10 The proposed framework is based on the evaluation of relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship, leading to a qualitative classification: "Definitive Evidence", "Strong Evidence", "Moderate Evidence", "Limited Evidence", "No Reported Evidence", or "Conflicting Evidence" (for details see ClinGen's Standard Operating Procedure (SOP) https://clinicalgenome.org/site/ assets/files/5391/gene_curation_sop_pdf-1.pdf). Only genes with a strong or definitive gene-disease association were included in our list of genes causing PD.      Alzheimer's disease Gene is linked to Alzheimer's disease; a few cases with prominent (spastic) ataxia have been described. Genes that have been associated with a movement disorder-predominant phenotype but did not meet the criteria for a confirmed genotype-phenotype relationship are listed as unconfirmed candidate genes (Supplementary material).

Applying the Recommendations
A full list of all genes, including genes previously included 3 (https://www.movementdisorders.org/MDS/ About/Committees-Other-Groups/MDS-Task-Forces/ Task-Force-on-Nomenclature-in-Movement-Disorders. htm) as well as yet unconfirmed candidate genes can be found in the Supplementary material (Tables S2-S7). Here we describe newly confirmed genes that cause movement disorders.

Genetically Determined Parkinsonism
The literature search for hereditary parkinsonism yielded >5000 publications in which genetic variants that are potentially associated with monogenic PD have been reported in over 80 genes. The majority of these genes have been reported only once, often in single sporadic cases, and thus remain to be confirmed (see Supplementary material). Twenty genes were already known causes of other non-parkinsonian disease entities; however, predominant features of typical or atypical parkinsonism have been described in several patients, indicating that the phenotypic spectrum of these entities should be expanded to include parkinsonism. Based on our criteria, these genes do not warrant a PARK prefix; however, for six of these genes, typical or atypical parkinsonism has been repeatedly reported to be a predominant feature in a subset of patients. Thus, we list C9orf72, DNAJC12, EPM2A, GRN, MAPT, and PDE8B in the category of genes that usually show a different phenotype but can have predominant parkinsonism in a subset of patients. Finally, 18 genes (Table 1 and Table S2) have been reported repeatedly in several unrelated patients or families, or by independent research groups, and were therefore classified as potential novel monogenic causes of parkinsonism.    Table 3 (ATX list) 551500 Variable phenotype predominantly including ataxia in the majority, but also myoclonus in a minority, for details see Table   3 mt EEF1A2  Chorea is rather equally prominent in respective cases, but this finding needs to be independently confirmed. This gene is currently in the list of unconfirmed candidate genes of hereditary chorea (Table S5)  Notably, several of these genes had already been assigned a PARK locus designation (by the previous ad hoc locus system). However, over time, follow-up studies and expert reviews have raised doubts and the evidence for many of these genes has been questioned. [11][12][13] For the majority of these genes, some of which were initially reported several years ago, the evidence is still not fully convincing or even became conflicting. A full list of genes still under debate can be found in the Supplementary material (Table S2). Based on our interpretation, supported by the ClinGen gene-disease curation criteria, we added four genes to the list of confirmed monogenic causes of parkinsonism. One of these genes, CHCHD2, causes typical levodopa-responsive parkinsonism very similar to idiopathic PD, whereas the other three, DCTN1, RAB39B, and VPS13C, cause a rather atypical parkinsonian phenotype with additional clinical features (Table 1). Interestingly, biallelic variants in the VPS13C gene have also been reported in patients with early-onset and autopsy-confirmed dementia with Lewy bodies (DLB), however, further research is necessary to confirm this association. 14 Additionally, four of the six genes that were previously listed as primary familial brain calcification genes were reclassified, and are now included in our updated list of hereditary parkinsonism ( Table 1). Two of these genes, JAM2 and SLC20A2, cause a phenotype with predominant atypical parkinsonism in the majority of cases and have therefore been assigned a PARK prefix, whereas another two, PDGFRB and XPR1, can include parkinsonian features but are insufficiently prominent to warrant a PARK prefix.

Genetically Determined Dystonia
We identified 21 new genes that warrant classification as causing dystonia (DYT). These genes have been organized into isolated dystonia, combined dystonia, and complex dystonia in accordance with the most recent guidelines 3 (Table 2). Within the complex dystonias, we highlight those genes associated with dystonia-deafness and dystonia with developmental delay since these combinations may be helpful genotype-phenotype relationships to consider when evaluating patients from a diagnostic standpoint. The frequent association of dystonia and neurodevelopmental disorders reflects the role of several of these genes in central nervous system development, and it is debatable whether to assign a DYT prefix (highlighting dystonia as a prominent feature) in the context of a neurodevelopmental disorder with developmental delay and/or intellectual disability. We suggest a DYT classification for three forms where dystonia is a predominant sign (IRF2BPL, VAC14, and FOXG1; Table 2). There are several genetic conditions where less prominent dystonia can be encountered in the setting of a predominant developmental disorder or epileptic encephalopathy. This combination can be diagnostically helpful, and we have designated these forms as "Neurodevelopmental disorder with dystonia" (Table S3A).
Finally, six additional genes have been reported in the literature as potential dystonia genes, namely TOMM70, COL6A3, NR4A2, POLR1C, NUBPL, and DEGS1; however, they currently lack independent confirmation and are therefore not (yet) included in our updated list of genetically determined dystonia (Table S3B).

Genetically Determined Ataxia
The ataxias are a clinically and genetically heterogeneous group of movement disorders. They can present as pure cerebellar ataxias with ataxia as the only or predominant feature or can be accompanied by variable additional signs and symptoms. We identified a total of 38 new genes known to cause monogenic ataxia and therefore assigned an ATX prefix. We categorized them based on their mode of inheritance: 11 genes are inherited in an autosomal dominant manner, 18 are inherited in an autosomal recessive fashion, and one each shows mitochondrial and X-linked inheritance. Further, another gene that was already known to cause autosomal recessive ataxia (ATX-STUB1, also known as SCAR16) and had therefore already been assigned a prefix, 4 has now also been confirmed as a dominant ataxia gene (also known as SCA48). Lastly, in ATX-MSTO1 also both autosomal dominant and recessive inheritance have been reported. The variable phenotypic spectrum of the listed genes is highlighted in Table 3. For five genes, a double prefix was assigned.
In addition to these confirmed genes, 95 genes have been reported as potential novel ataxia genes or genes causing a phenotype that can include ataxia. These await further confirmation (Table S4).

Genetically Determined Chorea
We expand our list of genetically determined chorea by adding five genes. Notably, four of these are related to combined phenotypes, specifically DYT and ATX (Table 4). One salient aspect of our literature review is the combination of chorea and developmental delay. Indeed, several entities characterized by motor, language, global delay, or epileptic encephalopathy are also associated with chorea, albeit in some cases in a less prominent manner. This is similar to our findings for dystonia genes and highlights the evolving spectrum of epilepsydyskinesia syndromes. 15 Table S5A lists genes linked to a neurodevelopmental disorder that can have chorea as part of their phenotype. Finally, three genes have been reported in the literature as potential chorea genes, PDE2A, GRIA3, and MRPL24; however, they lack independent confirmation (Table S5).

Genetically Determined Myoclonus
Myoclonus is a hyperkinetic movement disorder that is characterized by sudden, brief, involuntary jerks of single or multiple muscles. 5, 16 In addition, there are genetic myoclonic epilepsy syndromes, specifically the progressive myoclonus epilepsies and epileptic encephalopathies, where myoclonic jerks co-occur with epilepsy. There are many genetic disorders that include myoclonus but not as the only or most prominent feature.
Our literature review led us to assign a MYC-prefix to seven additional genes (Table 5), DHDDS, GRIA3, MFSD8, SEMA6B, SCN8A, and NUS1, three of which (SCN8A, KCTD17, and NUS1) have been assigned a combined prefix since paroxysmal movements, dystonia, and ataxia frequently coexist with myoclonus in these disorders. Notably, all these genes can cause a broad clinical phenotypic spectrum. Table 5 includes a list of genetic disorders that more commonly present with other phenotypes and do not warrant a MYC-prefix. A list of all genes which we identified for which myoclonus has been repeatedly reported, but neither as the prominent feature in the majority nor as the sole feature even in the minority of patients, can be found in the Supplementary material (Table S6A). Finally, another five genes have been reported in the literature as potential newly identified myoclonus genes, namely BOLA3, HCN4, KCNN2, MT-TN, and NUP214; however, they lack independent confirmation (Table S6B).

Hereditary Spastic Paraplegia (HSP)
The hereditary spastic paraplegias (HSP) can present as pure or complicated/complex forms with variable additional associated features such as cerebellar signs, neuropathy, cognitive impairment, seizures, optic nerve atrophy, or ophthalmoplegia. Our literature review resulted in the addition of 13 newly confirmed HSP genes ( Table 6). Two of them (CPT1C and UBAP1) are inherited in an autosomal dominant fashion and present as pure forms, whereas the others, except for one X-linked gene (SLC16A2), are inherited in an autosomal recessive fashion and present with a complex phenotype (ENTPD1, HPDL, MAG, PCYT2, and RNF170). One form, ALDH18A1, has both autosomal dominant and autosomal recessive inheritance. Further, four genes have been assigned a combined prefix, all of which can cause a broad and variable phenotypic spectrum including two predominant movement disorder phenotypes each; specifically ataxia and spastic paraplegia in HSP/ATX-CAPN1, HSP/ATX-UCHL1, ATX/HSP-KCNA2, and ATX/HSP-VPS13D. Additionally, another 20 genes have been reported in the literature as potential HSP genes; however, they lack independent confirmation and are therefore not (yet) included in our updated list. The list of unconfirmed candidate genes can be found in the Supplementary material (Table S7).

Genetically Determined Paroxysmal Movement Disorders
In our 2016 review, we introduced the category of Paroxysmal Movement Disorders (PxMD) which describes cases where movement disorders occur in an episodic manner. These disorders often include a mixed and overlapping phenomenology. Table 7 shows the proposed list of additional genetic paroxysmal movement disorders. We have conferred a PxMD prefix to the KCNMA1 gene which causes dystonic and choreiform movements. In some individuals, episodes happen without a clear trigger. We also included the ECHS1 gene that has been reported to cause episodic dystonia triggered by fever, stress, and physical activity. 17 Additionally, for SCN8A a double prefix has been assigned as mutations in this gene can either cause paroxysmal movements within a broad phenotypic spectrum of seizure disorders or familial myoclonus (Tables 5 and 7).
Genetically Determined Neurodegeneration with Brain Iron Accumulation (NBIA) and Primary Familial Brain Calcification (PFBC) As stated above, we decided to reclassify genes that have previously been assigned a NBIA or PFBC prefix according to their most prominent movement disorder phenotype. Two of these genes, XPR1 and PDGFRB, have lost their preceding prefix since the current evidence shows a movement disorder is present in a minority of individuals only. For both genes, however, parkinsonism has been described as a prominent feature in a subset of patients (see Table 1). Table S8 shows a complete list of all reclassified entities and summarizes all genes with a PBFC and NBIA suffix, respectively.

Genetically Determined Mixed Movement Disorders
Some genes display a mixed and overlapping phenomenology, without a clear predominance of a specific movement disorder. Given this, we propose a new category of Mixed Movement Disorders (MxMD). This list includes ATP13A2, OPA3, as well as POLG, and further also PDGFB and MYORG, both of which were in the previously existing category of primary familial brain calcification. Finally, ADCY5 was moved to this category; it was previously listed with three prefixes (CHOR/DYT/PxMD-ADCY5; https://www.movement disorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm).

Discussion
We here provide updated lists of hereditary movement disorders following the established procedure of the MDS Task Force for the Nomenclature of Genetic Movement Disorders. Our update covers the past 5 years and we have identified 89 new genes that warrant a movement disorder-related prefix. We believe that this is a helpful resource for clinicians and researchers, and we encourage the field to continue to adopt and use this nomenclature system. Along these lines, this project remains a moving target with need for continuous updates. We expect that many additional disease-causing genes will be identified and will need to be evaluated. We also expect that genes already assigned a prefix will need to be reassessed and may be reclassified over time. We will strive to continue to expand and improve our recommendations as the Task Force continues its assigned mandate, and yearly updates will be made available on the MDS Task Force website (https://www.movementdisorders.org/MDS/About/ Committees-Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm).

Challenges and Limitations
One of the main challenges we encountered when preparing these updated lists was determining the predominant phenotype in a given condition. This becomes especially challenging in very complex genetic syndromes and disorders with a broad phenotypic spectrum, for example, neurodevelopmental disorders or in the case of pronounced phenotypic variability (chameleon-like gene-disease relationships). From a clinical perspective, one might argue that genes should only be included if the respective movement disorder is the most prominent phenotype. Otherwise, the lists might get too extensive and then fail to usefully highlight any particular disorder. However, from a genetics perspective, it might make sense to include all genes that may present with a movement disorder in broader genetic testing efforts, even if it is not the predominant phenotype or if it is just in the minority of cases. This would ensure that physicians are aware of the phenotypic spectrum of a mutated gene and would be of more practical use to physicians seeing patients first presenting with movement disorders independent of whether this is a common or rare manifestation of the disorder. Recognizing the advantages of both approaches, we provide both a concise list that highlights those disorders where movement disorders predominate and a more comprehensive list of genes that usually present with other phenotypes or are even confirmed genes for a different disease entity, but where a movement disorder has been described. To distinguish the two, the latter genes were not assigned a prefix. We acknowledge that some of these "less predominant" cases may be the ones that are referred to a movement disorders specialist. Nonetheless, we believe that including them as part of the Supplementary material still provides a useful resource for the clinician. In this current update, we started by highlighting conditions that predominantly present as a neurodevelopmental disorder but can also have dominant dystonia and chorea. For future updates, it might be useful to apply this categorization also to other movement disorders, for example, ataxia and HSP. Additionally, in the future, we may consider assigning a special prefix to these genes. For example, to distinguish phenotypic presentations occurring in more than 50% and less than 50% of cases, one option under consideration is to retain the uppercase phenotype designation (eg, PARK, DYT, ATX, etc.) followed by the gene name for the former situation (as in the current classification) and to use a lowercase symbolization (eg, park, dyt, atx) for the latter.
Further, especially for newly identified genes, the initial publications often include patients with a broad phenotype and only over time, the "pure movement disorder phenotypes" or "core phenotypes" become apparent. In some cases, initial publications may report a pure movement disorder phenotype, and only over time and additional cases recurrent additional features may be identified. Finally, even with considerable further experience, for some genetic disorders it may remain impossible to define only a single (core) phenotype if great heterogeneity remains present.
Another challenge that arose in the preparation of this update was the evaluation of pathogenicity and what to consider to be convincing evidence for a causal gene-disease association. Our evaluation of pathogenicity was based on numerous criteria, the most important of which was an independent confirmation of a causal role of a gene in multiple unrelated patients or families and, in addition, the lack of evidence that refutes a causal gene-disease relationship. In general, this approach works well for rare diseases, which comprise the majority of genetic movement disorders described here. A particular challenge, however, was the evaluation of newly identified genes causing parkinsonism. PD is a common neurodegenerative disease. Thus, even two independent groups reporting variants in the same gene in single(ton) cases with typical PD and absence of specific additional features would not necessarily constitute enough evidence to be convincing as a monogenic cause of PD. Evidence of segregation in extended families and gene-specific functional studies on the other hand can help to support a causal relationship.
To overcome this obstacle, we employed standardized, previously published criteria. 6 These criteria served as presumably objective guidance in the interpretation of evidence for a gene-disease association based on currently available data; however, there remained room for subjective interpretation. Of note, these criteria set a high threshold, especially regarding the number of reported mutation carriers, to confirm a causal relationship. Given this, our list of unconfirmed genes (Table S2) serves as an important adjunct resource. Several genes already designated as PARK by the previous ad hoc locus system, for example, UCHL1, GIGYF2, HTRA2, EIF4G1, and DNAJC13 (termed as PARK5, PARK11, PARK13, PARK18, and PARK21, respectively), could not be confirmed. Of note, these genes are already being widely and mostly controversially discussed in the literature. 11,12 After the initial nomination of these genes as "novel PD genes", additional studies failed to confirm a causative role and pointed out that the existing evidence was conflicting (for details see Table S2). It has even been suggested to remove the PARK designation for these genes. 13 This experience reinforces the importance of standard criteria for inclusion in the PARK list. Based on these criteria, CHCHD2 and VPS13C (also known as PARK22 and PARK23, respectively) are now listed as confirmed causes of monogenic parkinsonism due to several reported patients, often with clearly truncating variants, especially in VPS13C (see Table 1).
With the support of the Parkinson's Foundation in the US, a PD Gene Curation Expert Panel (GCEP) comprising experts in clinical and molecular genetics of PD has been officially convened as a ClinGen Clinical Domain Working Group (https://clinicalgenome.org/affiliation/ 40079/). The PD GCEP has already begun to curate the well-established PD genes such as LRRK2 and VPS35 using the ClinGen framework and will additionally evaluate genes with a lower confidence of gene-disease association. As the work of the PD GCEP continues and more data become available in the literature, we will evaluate any potential discrepancies within the PD GCEP with our determinations and address them collaboratively before including them on the Task Force's homepage. Indeed, several of our Task Force members are also members of the PD GCEP, which will facilitate this dialogue. With respect to other movement disorders with a particular focus on rare movement disorders, the utility and feasibility of using the ClinGen framework still need to be determined. If deemed helpful, we may seek to establish new GCEPs for these conditions.

What's Next?
We expect that the list of newly identified genes linked to a movement disorder phenotype will continue to expand and simultaneously hopefully also our understanding of gene-disease associations. Therefore, it remains important to re-evaluate the literature periodically and update the lists of (confirmed) monogenic causes of movement disorders. These updated lists will then be published on the MDS Task Force website (https://www.movementdisorders.org/MDS/About/ Committees-Other-Groups/MDS-Task-Forces/Task-Forceon-Nomenclature-in-Movement-Disorders.htm). To make this easier, we have already started to prepare lists of yet unconfirmed candidate genes for the future.
To further define the phenotypic spectrum and genotype-phenotype correlations of these movement disorder genes, the Movement Disorder Society Genetic Mutation Database (MDSGene; https://www.mdsgene.org) provides the infrastructure for a systematic collection, curation, and descriptive analysis of phenotypic and genotypic data. Each of these newly defined movement disorders genes are candidates for inclusion in MDSGene and can provide new insights into the phenotype through the comprehensive individual-level nature of the data collection. We aim to expand the number of included genes in the MDSGene database and will start this effort by prioritizing novel monogenic causes of parkinsonism and dystonia.