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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 The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the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.

SUBMITTER: Christensen MB

PROVIDER: S-EPMC9546172 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Christensen Maria B MB Levy Amanda M AM Mohammadi Nazanin A NA Niceta Marcello M Kaiyrzhanov Rauan R Dentici Maria Lisa ML Al Alam Chadi C Alesi Viola V Benoit Valérie V Bhatia Kailash P KP Bierhals Tatjana T Boßelmann Christian M CM Buratti Julien J Callewaert Bert B Ceulemans Berten B Charles Perrine P De Wachter Matthias M Dehghani Mohammadreza M D'haenens Erika E Doco-Fenzy Martine M Geßner Michaela M Gobert Cyrielle C Guliyeva Ulviyya U Haack Tobias B TB Hammer Trine B TB Heinrich Tilman T Hempel Maja M Herget Theresia T Hoffmann Ute U Horvath Judit J Houlden Henry H Keren Boris B Kresge Christina C Kumps Candy C Lederer Damien D Lermine Alban A Magrinelli Francesca F Maroofian Reza R Vahidi Mehrjardi Mohammad Yahya MY Moudi Mahdiyeh M Müller Amelie J AJ Oostra Anna J AJ Pletcher Beth A BA Ros-Pardo David D Samarasekera Shanika S Tartaglia Marco M Van Schil Kristof K Vogt Julie J Wassmer Evangeline E Winkelmann Juliane J Zaki Maha S MS Zech Michael M Lerche Holger H Radio Francesca Clementina FC Gomez-Puertas Paulino P Møller Rikke S RS Tümer Zeynep Z

Clinical genetics 20220608 2

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 c ...[more]

PMID: 35616059

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Project description:Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid metabolism. Cardiolipin, the signature phospholipid of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesized and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to cardiolipin biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human cardiolipin-related PMDs are not fully characterized. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterized the molecular defects associated with mutant PTPMT1 and confirmed the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterize the functional role of PTPMT1 in cardiolipin homeostasis, we created a ptpmt1 knockout zebrafish. This model had abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired cardiolipin metabolism, highlighting the contribution of aberrant cardiolipin metabolism towards human disease and emphasizing the importance of normal cardiolipin homeostasis during neurodevelopment.

Dataset Information

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Publications

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

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