Publications by authors named "Anita Rauch"

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder.

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  • This study identifies a new type of autosomal recessive intellectual disability linked to genetic variants in the GTF3C3 gene, which is essential for proper RNA polymerase III activity.
  • Researchers employed various methods, including exome sequencing and Drosophila models, to analyze the effects of GTF3C3 variants found in twelve affected individuals from seven families.
  • The results showed that the variants lead to significant functional losses in the gene, correlating with symptoms like intellectual disability, motor issues, seizures, and brain structure abnormalities.
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  • - This study examines the link between rare variants in the cullin-3 ubiquitin ligase (CUL3) gene and neurodevelopmental disorders (NDDs), gathering data from multiple centers to explore genetic mutations and their clinical impacts.
  • - Researchers identified 37 individuals with CUL3 variants, most of which result in loss-of-function (LoF), leading to intellectual disabilities and possibly autistic traits; specific mechanisms affecting protein stability were also investigated.
  • - The findings enhance the understanding of NDDs associated with CUL3 mutations, suggesting that LoF variants are the main cause, which could help inform future diagnostics and treatment strategies.
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  • Zinc and RING finger 3 (ZNRF3) regulates Wnt/β-catenin signaling, crucial for brain development, but germline variants have not been linked to neurodevelopmental disorders (NDDs) before.
  • Researchers found 12 individuals with ZNRF3 variants, noting a correlation between specific mutations and NDD phenotypes, especially those affecting brain size.
  • Structural modeling and functional assays revealed that missense variants linked to larger brain size enhanced Wnt signaling, while a variant causing smaller brain size reduced it, indicating different mechanisms at play in NDDs related to ZNRF3 mutations.
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  • Alterations in the DMD gene lead to dystrophinopathies that can cause diseases like Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), as well as other issues such as heart problems and intellectual disabilities.
  • Carrier females usually don't show symptoms but can still have some signs of these conditions; some male carriers also appear asymptomatic but may have elevated creatine kinase due to specific genetic deletions.
  • A case study of a family with a deletion of exon 48 of the DMD gene supports the idea of a genotype-phenotype correlation but highlights the need for more research to understand how genetic variations influence disease expression accurately.
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Objectives: To present a case series of novel variants in patients presenting with genetic epileptic and developmental encephalopathy.

Background: CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders.

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Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows. This includes extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUSs) are a challenge to personalized medicine.

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Deubiquitination is crucial for the proper functioning of numerous biological pathways, such as DNA repair, cell cycle progression, transcription, signal transduction and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders and congenital abnormalities. ATXN7L3 is a component of the DUB module of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex and two other related DUB modules, and it serves as an obligate adaptor protein of three ubiquitin-specific proteases (USP22, USP27X or USP51).

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Anoctamins are a family of Ca-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure.

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To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which localized in the PHD1/PHD2 domains of DPF2. Here we report on the first familial case of Coffin-Siris syndrome type 7.

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  • SNURPORTIN-1 (SNUPN) is important for transporting proteins in the cell but its exact job wasn’t known before.
  • Researchers studied 18 kids with a rare type of muscular dystrophy and found that changes in the SNUPN gene might be causing their health issues.
  • The study showed that the faulty SNUPN protein doesn't work properly, leading to problems in muscle cells and causing symptoms of muscular dystrophy in these kids.
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  • * Researchers found 23 specific changes in a gene related to this complex that affect 38 people, leading to problems with brain cell growth and learning in animals.
  • * By targeting certain stress response proteins, they discovered ways to help fix some of the immune issues caused by these disorders, leading to new ideas for treatments.
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Somatic variants in the NOTCH pathway regulator FBXW7 are frequently seen in a variety of malignancies. Heterozygous loss-of-function germline variants in FBXW7 have recently been described as causative for a neurodevelopmental syndrome. Independently, FBXW7 was also considered as a susceptibility gene for Wilms tumor due to a few observations of heterozygous germline variants in patients with Wilms tumor.

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  • - PhenoScore is an open-source AI framework that combines facial recognition technology and Human Phenotype Ontology data to analyze and quantify phenotypic similarities in individuals.
  • - It successfully identifies distinct phenotypes for most of the 40 syndromes studied and proves to be more effective than previous methods in genotype-phenotype correlation investigations.
  • - PhenoScore also helps clarify roles of specific genetic variants by confirming known phenotypic subgroups in certain genes and providing clinical evidence for different ADNP-related phenotypes.
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MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants.

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  • Costello syndrome is a severe neurodevelopmental disorder linked to changes in the HRAS gene, mostly involving codons 12 and 13, leading to a consistent phenotype in affected individuals.
  • This report discusses a unique subgroup from one family with a less severe form linked to a specific HRAS variant (c.176C>T p.(Ala59Gly)), which hasn't been documented before in other patients.
  • The individuals exhibit mild ectodermal issues and show no major health concerns, pointing to a new, milder form of HRAS-related disorders compared to classical Costello syndrome, suggesting the need for a new classification for such cases.
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Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings.

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  • The blood-brain barrier (BBB) regulates the central nervous system and is linked to neurodevelopmental disorders (NDDs), especially in infants with intracerebral hemorrhage (ICH).
  • Researchers identified a rare disease trait in 13 individuals from 8 families due to a genetic variant in the ESAM gene, affecting endothelial cell function and leading to developmental issues.
  • The study highlights the connection between endothelial dysfunction and NDDs, suggesting the emergence of a new category of diseases called "tightjunctionopathies."
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  • Pathogenic variants in KMT5B, a lysine methyltransferase, are linked to global developmental issues, macrocephaly, autism, and other congenital anomalies, but the disorder is still not fully understood.
  • A study examining 43 patients revealed new significant features like hypotonia and congenital heart defects not previously associated with this condition.
  • Research using patient cell lines and KMT5B knockout mice showed that these variants lead to slow growth and highlighted alterations in pathways related to nervous system development, enhancing our understanding of the disorder's molecular mechanisms.
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Background: As the technology of next generation sequencing rapidly develops and costs are constantly reduced, the clinical availability of whole genome sequencing (WGS) increases. Thereby, it remains unclear what exact advantage WGS offers in comparison to whole exome sequencing (WES) for the diagnosis of genetic diseases using current technologies.

Methods: Trio-WGS was conducted for 20 patients with developmental or epileptic encephalopathies who remained undiagnosed after WES and chromosomal microarray analysis.

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Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants.

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  • Next generation sequencing (NGS) can identify carrier status for rare recessive disorders, helping couples understand their reproductive risks, in line with ACMG recommendations for broad carrier screening based on gene frequency.
  • In a study of 118 ciliopathy genes, researchers found that 20% of healthy individuals and 50% carried variants of uncertain significance (VUS), complicating the interpretation of NGS results due to limitations in variant classification criteria.
  • The findings highlight a need for better understanding of gene-specific variant patterns and emphasize the importance of transparent genetic counseling to inform individuals about the challenges and uncertainties inherent in NGS-based carrier screening.
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