Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder

Abstract

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying

Focal Head Tremor and ZNF142‐Associated Neurodevelopmental Disorder

“…(A) Slightly irregular "no-no" type of tremor; (B) slight head tremor in the primary position which abolished when the patient turns his head fully to the right, without signs of overt dystonia. It might be argued that a (dubious) head rotation is visible in the primary position at beginning of (B); however we note that (1) this is an inconstant feature as it is not present throughout the video, especially after the patient rotates his head to return in the primary position; (2) there are no patterned rotational movements of the head; and (3) there is no range-of-motion restriction on either side when turning the head. As such the, admittedly mild, and inconstant rotation of the head could be a compensatory habit to reduce the tremor.…”

“…Movement disorders have been reported in 36-56% in individual reports, 1,7 but they seem overall to account for a lower percentage of patients with biallelic variants of ZNF142 (eg, 25%; Table S1). 1,[7][8][9][10] Movement disorders most commonly encompass tremor, ataxia, and dystonia, but also paroxysmal movement disorders akin to paroxysmal exercise-induced dystonia and episodic ataxia (Table S1).…”

“…Clear genotype-phenotype correlations have not been established yet because, apart from few cases carrying missense variants and having a milder phenotype, most reported patients carry truncating variants (Table S1). 1,[7][8][9][10] Moreover, in the absence of experimental information about the function and localization of ZNF142, it is difficult to speculate on exact genotype-phenotype correlations.…”

“…Movement disorders have been reported in 36-56% in individual reports, 1,7 but they seem overall to account for a lower percentage of patients with biallelic variants of ZNF142 (eg, 25%; Table S1). 1,[7][8][9][10] Movement disorders most commonly encompass tremor, ataxia, and dystonia, but also paroxysmal movement disorders akin to paroxysmal exercise-induced dystonia and episodic ataxia (Table S1). Clear genotype-phenotype correlations have not been established yet because, apart from few cases carrying missense variants and having a milder phenotype, most reported patients carry truncating variants (Table S1).…”

A deleterious frameshift insertion mutation in the ZNF142 gene leads to intellectual developmental disorder with impaired speech in three affected siblings: Clinical features and literature review

“…In addition to the missed functional domains, the transcript could be exposed to the nonsense-mediated decay process, which shortens the half-life of the transcript (Holbrook et al, 2004). Moreover, the identified deleterious variant, NM_001379659.1 (ZNF142):c.3755dup, was recently reported from Iran on the same ethnicity group related to the same condition (Christensen et al, 2022), which might implicate it as a variant of the founder movement disorder, hypotonia, atonia, some facial features. Along with other studies, the patients in current study show intellectual disability, neurodevelopmental delay, delayed milestones, and speech impairments.…”