Background: 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 ZMIZ1 gene on chromosome 10q22.3 with autosomal dominant (AD) mode of inheritance. All the 32 reported cases with variants in ZMIZ1 gene had a genetic background in Caucasian, Hispanic, North African, and Southeastern Asian. Until now, there are no reports of Chinese patients with ZMIZ1 pathogenic variants.Methods: 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.Results: 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 de novo heterozygous missense variant (c.2330G > A, p.Gly777Glu, G777E) was identified in the exon 20 of ZMIZ1. No variants of ZMIZ1 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.Conclusion: Thus far, only four scientific articles reported deleterious variants in ZMIZ1 and most of the cases were from Western countries. This is the first report about a Chinese patient with ZMIZ1 variant. It will broaden the current knowledge of ZMIZ1 variants and variable clinical presentations for clinicians and genetic counselors.
Background Coffin–Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. CSS represents a small group of intellectual disability, and could be caused by at least twelve genes. The genetic background is quite heterogenous, making it difficult for clinicians and genetic consultors to pinpoint the exact disease types. Methods Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for three trios affected with intellectual disability and clinical features similar with those of Coffin–Siris syndrome. Sanger sequencing was used to verify the detected single-nucleotide variants (SNVs). Results All of the three cases were female with normal karyotypes of 46, XX, born of healthy, non-consanguineous parents. A 6q25 microdeletion (arr[hg19]6q25.3(155,966,487–158,803,979) × 1) (2.84 Mb) (case 1) and two loss-of-function (LoF) mutations of ARID1B [c.2332 + 1G > A in case 2 and c.4741C > T (p.Q1581X) in case 3] were identified. All of the three pathogenic abnormalities were de novo, not inherited from their parents. After comparison of publicly available microdeletions containing ARID1B, four types of microdeletions leading to insufficient production of ARID1B were identified, namely deletions covering the whole region of ARID1B, deletions covering the promoter region, deletions covering the termination region or deletions covering enhancer regions. Conclusion Here we identified de novo ARID1B mutations in three Chinese trios. Four types of microdeletions covering ARID1B were identified. This study broadens current knowledge of ARID1B mutations for clinicians and genetic consultors.
BackgroundFOXG1-related encephalopathy, also known as FOXG1 syndrome or FOXG1-related disorder, affects most aspects of development and causes microcephaly and brain malformations. This syndrome was previously considered to be the congenital variant of Rett syndrome. The abnormal function or expression of FOXG1, caused by intragenic mutations, microdeletions or microduplications, was considered to be crucial pathological factor for this disorder. Currently, most of the FOXG1-related encephalopathies have been identified in Europeans and North Americans, and relatively few Chinese cases were reported.MethodsArray-Comparative Genomic Hybridization (Array-CGH) and whole-exome sequencing (WES) were carried out for the proband and her parent to detect pathogenic variants.ResultsA de novo nonsense mutation (c.385G>T, p.Glu129Ter) of FOXG1 was identified in a female child in a cohort of 73 Chinese children with neurodevelopmental disorders/intellectual disorders (NDDs/IDs). In order to have a comprehensive view of FOXG1-related encephalopathy in China, relevant published reports were browsed and twelve cases with mutations in FOXG1 or copy number variants (CNVs) involving FOXG1 gene were involved in the analysis eventually. Feeding difficulties, seizures, delayed speech, corpus callosum hypoplasia and underdevelopment of frontal and temporal lobes occurred in almost all cases. Out of the 12 cases, eight patients (66.67%) had single-nucleotide mutations of FOXG1 gene and four patients (33.33%) had CNVs involving FOXG1 (3 microdeletions and 1 microduplication). The expression of FOXG1 could also be potentially disturbed by deletions of several brain-active regulatory elements located in intergenic FOXG1-PRKD1 region. Further analysis indicated that PRKD1 might be a cooperating factor to regulate the expression of FOXG1, MECP2 and CDKL5 to contribute the RTT/RTT-like disorders.DiscussionThis re-analysis would broaden the existed knowledge about the molecular etiology and be helpful for diagnosis, treatment, and gene therapy of FOXG1-related disorders in the future.
Wiedemann-Rautenstrauch syndrome (WDRTS) is an extremely rare autosomal recessive neonatal disorder. Currently, over 50 cases with variable phenotypes of WDRTS have been reported. In our cohort of prenatal and postnatal growth retardation, a female proband was found to have general growth retardation, neurocutaneous syndrome, and anemia. Karyotype test and array-CGH detected no obvious chromosomal aberrations. Trio-based whole-exome sequencing (Trio-WES) identified bi-allelic compound mutations in the coding sequence (CDS) of POLR3A gene (c.3342C > T, p.Ser1114 = and c.3718G > A, p.Gly1240Ser). For the mild anemia phenotype, the underlying causal genetic factors could be attributed to the compound heterozygous mutations in FANCA gene (c.2832dup, p.Ala945CysfsTer6 and c.1902 T > G, p.Asp634Glu). Mini-gene reporter assays revealed that the synonymous variant of POLR3A and the missense variant of FANCA could affect pre-mRNA splicing of each gene. For POLR3A, the synonymous mutation (c.3342C > T, p.Ser1114=) generated three types of aberrant isoforms. Therefore, the female patient was finally diagnosed as WDRTS caused by POLR3A. For FANCA, the missense variant (c.1902 T > G, p.Asp634Glu) disrupted the normal splicing between exon 21 and 22, and produced two types of abnormal isoforms, one carrying the 1902G and the other spliced between exon 21 and 23 to exclude exon 22. Network analysis showed that POLR3A and FANCA could be STRINGed, indicating both proteins might collaborate for some unknown functions. Current investigation would broaden the knowledge for clinicians and genetic counselors and remind them to interpret those synonymous or predicted “benign” variants more carefully.
Currently, majority of the FOXG1-related Rett syndrome have been identified in Europeans and North Americans, and relatively few Chinese cases were reported. We identified a de novo nonsense mutation of FOXG1 in a female child with Rett syndrome out of 73 Chinese children with neurodevelopmental disorders in our cohort. In order to have a comprehensive view of FOXG1-related disorders in China, relevant published reports were browsed and twelve cases with FOXG1 mutations or copy number variants (CNVs) involving FOXG1 gene were involved in the analysis eventually. Feeding difficulties, seizures, delayed speech, corpus callosum hypoplasia and underdevelopment of frontal and temporal lobes occurred in almost all cases. Out of the 12 cases, eight patients (66.67%) had single-nucleotide mutations (SNMs) of FOXG1 gene and four patients (33.33%) had CNVs involving FOXG1 (3 microdeletions and 1 microduplication). FOXG1 was the crucial pathological factor for FOXG1-related Rett disorder, which could be further regulated by the regulatory elements located in the intergenic region (FOXG1-PRKD1). Further analysis indicated that PRKD1 might be a contributor to the FOXG1-related Rett syndrome, which interacted with the upstream factors to regulate the expression of FOXG1, even MECP2 and CDKL5. This reanalysis might promote the existed knowledge about the molecular etiology and be helpful for diagnosis, treatment and gene therapy of FOXG1-related disorders in the future.
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