Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Kumar, Kishore R.; Davis, Ryan L.; Tchan, Michel; Wali, Gautam; Mahant, Neil; Ng, Karl; Kotschet, Katya; Siow, Sue Faye; Gu, Jason; Walls, Zachary F.; Kang, Ce; Levy, Stan; Phua, Chun Seng; Yiannikas, Con; Darveniza, Paul; Chang, Florence; Morales‐Briceño, Hugo; Rowe, Dominic B.; Drew, Alexander P.; Gayevskiy, Velimir; Cowley, Mark J.; Minoche, André E.; Tisch, Stephen; Hayes, Michael; Kummerfeld, Sarah; Fung, Victor S.C.; Sue, Carolyn M.

doi:10.1016/j.parkreldis.2019.11.004

Cited by 45 publications

(60 citation statements)

References 30 publications

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“…1,2 It is characterized by sustained or episodic muscle contractions, which cause abnormal, often repetitive movements and twisting postures affecting the limbs, trunk, neck, and face. 3 Despite significant advances in nextgeneration sequencing technologies, over 85% of people with suspected genetic dystonia remain undiagnosed after whole-genome sequencing, 4 implying that the majority of genetic dystonias currently remain unrecognized. The reasons for this are multifactorial, attributed to locus heterogeneity, incomplete disease penetrance, and the current limitations of next-generation sequencing technologies.…”

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confidence: 99%

Loss‐of‐Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Steel¹,

Zech²,

Zhao³

et al. 2020

Annals of Neurology

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ObjectivesThe majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses.MethodsWe undertook weighted burden analysis of whole‐exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case‐finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient‐derived cells.ResultsAnalysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome‐lysosome fusion. A total of 18 individuals harboring heterozygous loss‐of‐function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss‐of‐function variants in VPS41, another HOPS‐complex encoding gene, in an individual with infantile‐onset generalized dystonia. Electron microscopy of patient‐derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function.InterpretationOur study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867–877

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confidence: 99%

Loss‐of‐Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Steel¹,

Zech²,

Zhao³

et al. 2020

Annals of Neurology

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“…We report a video‐documented case of ADCY5 ‐related dyskinesia who was followed up for nearly 2 decades during which the phenotype of “ballistic bouts” evolved into a nonparoxysmal mixed‐motor disorder consisting of severe dystonia and gait abnormalities. Our patient carried a de novo missense variant NM_183357.2:c.3086T>A; p.Met1029Lys in the ADCY5 gene 5 …”

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confidence: 77%

Long‐Term Follow‐Up and Evolution of ADCY5—From a Ballistic to Dystonic Phenotype

Wali¹,

Kumar

Sue

2020

Movement Disord Clin Pract

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“…Other previously described neurologic features noted in the proband include dysfluency, bulbar dysfunction, dysphagia, intellectual disability, and developmental delay [5,6]. , Additional reported features not present include eye movement abnormalities, skin changes, psychiatric co-morbidities (anxiety, depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder), myoclonus, seizures, spasticity, sensorineural hearing loss, microcephaly, and parkinsonism [5,6,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…Our report describes the phenotype in a family with a previously undescribed KMT2B variant and highlights failure to thrive, an overlooked manifestation. Thus far, 80 additional patients have been described (Additional Table) [5,6,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. A recent report identified KMT2B mutations in 21.5% of patients with previously undiagnosed childhood-onset dystonia suggesting KMT2B mutations may be a relatively common cause of dystonia in children [26].…”

Section: Discussionmentioning

confidence: 99%

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

Galosi

Salz

et al. 2020

BMC Neurol

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Background: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this nonneurologic, but consequential impact of mutation in this gene. Case presentation: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. Conclusion: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.

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Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Cited by 45 publications

References 30 publications

Loss‐of‐Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Loss‐of‐Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Long‐Term Follow‐Up and Evolution of ADCY5—From a Ballistic to Dystonic Phenotype

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

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