A de Novo ZMIZ1 Pathogenic Variant for Neurodevelopmental Disorder With Dysmorphic Facies and Distal Skeletal Anomalies

Abstract

<b>Background:</b> Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a rare syndromic disorder characterized by global neurodevelopmental delay, early-onset hypotonia, poor overall growth, poor speech/language ability, and additional common phenotypes such as eye anomalies, joint hypermobility, and skeletal anomalies of the hands and feet. NEDDFSA is caused by heterozygous pathogenic variants in the <i>ZMIZ1</i> gene on chromosome 10q22.3 with autosomal dominant (AD) mode of inheritance. All the 32 reported cases with variants in <i>ZMIZ1</i> gene had a genetic background in Caucasian, Hispanic, North African, and Southeastern Asian. Until now, there are no reports of Chinese patients with <i>ZMIZ1</i> pathogenic variants. <b>Methods:</b> A 5-year-old girl was found to have the characteristic phenotypes of NEDDFSA. Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for the trio of this female patient. Sanger sequencing was used to verify the selected variants. A comprehensive molecular analysis was carried out by protein structure prediction, evolutionary conservation, motif scanning, tissue-specific expression, and protein interaction network to elucidate pathogenicity of the identified ZMIZ1 variants. <b>Results:</b> The karyotype was 46, XX with no micro-chromosomal abnormalities identified by array-CGH. There were 20 variants detected in the female patient by WES. A <i>de novo</i> heterozygous missense variant (c.2330G > A, p.Gly777Glu, G777E) was identified in the exon 20 of <i>ZMIZ1</i>. No variants of <i>ZMIZ1</i> were identified in the non-consanguineous parents and her healthy elder sister. It was predicted that G777E was pathogenic and detrimental to the spatial conformation of the MIZ/SP-RING zinc finger domain of ZMIZ1. <b>Conclusion:</b> Thus far, only four scientific articles reported deleterious variants in <i>ZMIZ1</i> and most of the cases were from Western countries. This is the first report about a Chinese patient with <i>ZMIZ1</i> variant. It will broaden the current knowledge of ZMIZ1 variants and variable clinical presentations for clinicians and genetic counselors.