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 degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Keywords: ZNF142; epilepsy; intellectual disability; language impairement; movement disorder; neurodevelopmental disorder.

FIGURE 1

Facial photographs of the individuals carrying biallelic pathogenic variants in ZNF142. Age of the individuals (ind) when photographed: Ind 2, 17 years; Ind 5, 17 years in middle and right photographs, age unknown in left photograph; Ind 6, 14 years in middle and right photographs, age unknown in left photograph; Ind 11, 5 years; Ind 12, 20 years; Ind 16, 10 years; Ind 17, 18 months; Ind 22, 3 years; Ind 23, 22 years; Ind 31, 12 years; Ind 34, 15 years; Ind 35, 9 years. Fam, Family [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Schematic illustration of the location of each ZNF142 variant at protein (left) and DNA (right) levels. (Left) Each light gray box represents one of the 31 ZF motifs. (Middle) Underlined text: Homozygous variant. Nonunderlined text: Compound heterozygous variant in trans with the variant with the same roman numeral. Underlined, bold, italic text: Detected as homozygous and compound heterozygous variant in trans with the variant with the same roman numeral; (Right) The dark gray boxes represent ZNF142 exons. The narrow boxes represent the untranslated regions. N, N‐terminal; C, C‐terminal

FIGURE 3

Structural model of the missense variants of ZNF142. (A) Structural model of ZF motifs 18–26 (ZF18 ‐ ZF26) of the protein and their interaction with DNA. Zn²⁺ ions are represented as gray spheres. The positions of the residues Cys1233, Phe1295, and Arg1500 are indicated. (B) Multiple sequence alignment of the 17 C‐terminal ZF motifs. The positions of Cys1233 (ZF18), Phe1295 (ZF20), and Arg1500 (ZF26) are shown in red. In green, the Cys and His residues that coordinate the Zn²⁺ ion (among them, Cys1233). In yellow, positions homologous to Phe1295 that are conserved. In blue, conserved positions with positive electrostatic charge homologous to Arg1500. (C) Position of Cys1233 coordinating the Zn²⁺ ion. The Cys1233Phe substitution would completely disorder the structure of ZF18. (D) Position of Phe1295 stabilizing the position of His1304, which, in turn, coordinates the Zn²⁺ ion. (E) Position of Arg1500 associating with the DNA phosphate chain. The Arg1500Trp substitution would prevent the correct interaction of ZF26 with DNA [Colour figure can be viewed at wileyonlinelibrary.com]