Three generation families: Analysis of de novo variants in autism

Costa, Claudia Ismania Samogy; Campos, Gabriele; Montenegro, Eduarda Morgana da Silva; Wang, Jaqueline Yu Ting; Scliar, Marília de Oliveira; Monfardini, Frederico; Zachi, Elaine Cristina; Lourenço, Naila Cristina Vilaça; Chan, Ada J.S.; Pereira, Sérgio Luiz; Engchuan, Worrawat; Thiruvahindrapuram, Bhooma; Zarrei, Mehdi; Scherer, Stephen W.; Passos‐Bueno, Maria Rita

doi:10.1038/s41431-023-01398-6

Cited by 3 publications

(1 citation statement)

References 32 publications

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“…Compared with this, synthetic engineering may be advantageous if gene acts as a master regulator with prognostic significance. In psychiatric disorders, ZNF537/TSHZ3 and ZNF536 were expressed in the cerebral cortex, and supported by CRISPR information [ 40 ]. Indeed, targeted design for ZNF536 are beyond the manuscript’s scope.…”

Section: Discussionmentioning

confidence: 99%

Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis

Zeng,

Zhang,

Yin

et al. 2024

Eur J Med Res

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Background Previous studies suggested that zinc finger protein 536 (ZNF536) was abundant in the central brain and regulated neuronal differentiation. However, the role of ZNF536 in cancer has remained unclear. Methods ZNF536 mutation, copy number alteration, DNA methylation, and RNA expression were explored using public portals. Data from The Cancer Genome Atlas (TCGA) were utilized to analyze pathways and tumor microenvironment (TME), with a focus on prognosis in both TCGA and immunotherapy pan-cancer cohorts. Methylated ZNF536 from small cell lung cancer (SCLC) cell lines were utilized to train with probes for conducting enrichment analysis. Single-cell RNA profile demonstrated the sublocalization and co-expression of ZNF536, and validated its targets by qPCR. Results Genetic alterations in ZNF536 were found to be high-frequency and a single sample could harbor different variations. ZNF536 at chromosome 19q12 exerted a bypass effect on CCNE1, supported by CRISPR data. For lung cancer, ZNF536 mutation was associated with longer survival in primary lung adenocarcinoma (LUAD), but its prognosis was poor in metastatic LUAD and SCLC. Importantly, ZNF536 mutation and amplification had opposite prognoses in Stand Up To Cancer-Mark Foundation (SU2C-MARK) LUAD cohort. ZNF536 mutation altered the patterns of genomic alterations in tumors, and had distinct impacts on the signaling pathways and TME compared to ZNF536 amplification. Additionally, ZNF536 expression was predominantly in endocrine tumors and brain tissues. High-dimensional analysis supported this finding and further revealed regulators of ZNF536. Considering that the methylation of ZNF536 was involved in the synaptic pathway associated with neuroendocrine neoplasms, demonstrating both diagnostic and prognostic value. Moreover, we experimentally verified ZNF536 upregulated neuroendocrine markers. Conclusions Our results showed that ZNF536 alterations in cancer, including variations in copy number, mutation, and methylation. We proved the involvement of ZNF536 in neuroendocrine regulation, and identified highly altered ZNF536 as a potential biomarker for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis

Zeng,

Zhang,

Yin

et al. 2024

Eur J Med Res

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Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates

Viggiano,

Ceroni,

Visconti

et al. 2024

npj Genom. Med.

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in the cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 8 severe de novo pdSNVs in genes not previously implicated in ASD (AGPAT3, IRX5, MGAT5B, RAB8B, RAP1A, RASAL2, SLC9A1, YME1L1) highlighted promising candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, although this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in ASD/NDD candidate genes not yet established. In conclusion, our study highlights promising ASD candidate genes and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

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Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease

Lopes-Marques,

Mort,

Carneiro

et al. 2024

Hum Genomics

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Background De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories. Results Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations. Conclusion This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.

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Three generation families: Analysis of de novo variants in autism

Cited by 3 publications

References 32 publications

Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis

Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis

Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates

Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease

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