Objective: To identify a novel genetic factor contributing to the phenotypic expression of early-onset generalized dystonia.

Background: To date, only about 20-30% of cases with generalized dystonia can be solved molecularly, indicating that additional genetic etiologies remain to be discovered. Determining new genetic causes of dystonia is of tremendous importance for defining underlying molecular pathways and translating mechanistic insights into clinical care.

Method: We performed in-depth clinical phenotyping for three case subjects with infancy-onset generalized dystonia from two independent families (families 1 and 2). Analysis of whole-exome sequences was undertaken in affected and unaffected family members, including a comprehensive search for known and potentially novel dystonia-associated variants. To evaluate the role of the prioritized variant-harboring gene, we thoroughly interrogated online data repositories.

Results: Whereas our cases harbored no clearly pathogenic variants in known dystonia-causing genes, our filtering strategy enabled the prioritization of deleterious biallelic alterations – a homozygous nonsense variant (p.Arg1059X; family 1) and two compound heterozygous frameshift variants (Lys273GlufsX32, p.Cys431LeufsX11; family 2) – in ZNF142, a gene not previously implicated in human disease. All variants were expected to introduce premature termination codons, predictive of complete loss of ZNF142 function in the dystonia cases. ZNF142 encodes a Cys2His2-type zinc finger transcription factor, with highest expression reported in the brain, specifically the cerebellum. Suggestive of an indispensable role for ZNF142 in the nervous system, mouse mutants with homozygous ablation of the orthologous locus (Zfp142) are reported to display significant neurological impairment. Clinically, our cases demonstrated generalized dystonic movements involving the extremities, trunk, and craniocervical regions, accompanied by speech problems, ataxia, and variable intellectual disability.

Conclusion: Our data suggest that deficiency of a ZNF142-encoded transcriptional regulator is an excellent candidate for disease causation in generalized dystonia. We would like to share our findings with the Movement Disorders community in order to promote the identification of additional individuals with biallelic ZNF142 mutations and confirm ZNF142 as a new dystonia-linked gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/biallelic-znf142-null-mutations-in-patients-with-early-onset-generalized-dystonia/