Publications by authors named "Maja Hempel"

Purpose: Although chromosome 21 is the smallest human chromosome, it is highly relevant in the pathogenicity of both cancer and congenital diseases, including Alzheimer disease and trisomy 21 (Down syndrome). In addition, cases with rare structural variants (SVs) of chromosome 21 have been reported. These events vary in size and include large chromosomal events, such as ring chromosomes and small partial aneuploidies.

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  • - The study aimed to find genetic variants causing multiple arterial aneurysms by analyzing a cohort of 2,189 patients after excluding those with known hereditary conditions.
  • - Whole exome sequencing of blood samples revealed 24 variants across 23 genes linked to vascular diseases, including significant findings for genes SMAD3, TNXB, and TET2, each linked to different syndromes and risks.
  • - All nine patients analyzed had gene variants recognized as associated with vascular diseases, highlighting the genetic underpinnings of multiple arterial aneurysms.
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  • * A 3-year study, TRANSLATE NAMSE, analyzed data from 1,577 patients, revealing that 32% received molecular diagnoses involving 370 distinct causes, primarily uncommon.
  • * The research showed that combining next-generation sequencing with advanced phenotyping methods improved diagnostic efficiency and helped identify new genotype-phenotype associations, particularly in neurodevelopmental disorders.
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  • Autism is a common condition influenced by both single gene issues and multiple genes, and many autistic people need better healthcare that genomics can help provide.
  • The European Autism GEnomics Registry (EAGER) aims to collect info about autistic people who have had their entire DNA sequenced to help with future research and trials.
  • EAGER will involve 1,500 participants from 13 places in 8 countries who will share genetic samples and fill out surveys to help researchers understand the link between genetics and health.
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Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene-disease lists from gNBS studies, evaluating gene-disease count, composition, group proportions, and ClinGen curations of individual disorders.

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Purpose: Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4 cells.

Methods: The CRISPR-a gene activation screen utilized sgRNAs from the promoters of protein-coding genes.

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Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease.

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  • - Pediatric acute liver failure (PALF) is a serious condition with up to 50% of cases remaining unexplained, hindering effective treatment options like liver transplantation.
  • - In a study involving 260 children from 19 countries, whole-exome sequencing (WES) identified genetic causes in 37% of indeterminate PALF cases, with a particularly high diagnostic rate in infants and those with recurrent liver failure.
  • - The research uncovered 36 distinct genes associated with PALF, highlighting mitochondrial diseases as the most common cause and underscoring the need for advanced genetic testing in diagnosing and treating this condition.
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  • The protein ACBD6 is important for lipid and protein acylation, but its exact role and effects of its defects on human health remain unclear.
  • Researchers found 45 individuals from 28 families with harmful mutations in ACBD6, leading to a variety of severe developmental and movement disorders.
  • Model organisms like zebrafish and Xenopus were used in studies to better understand ACBD6's function in protein modification and its localization in peroxisomes, which could help explain the associated disease symptoms.
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Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies.

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  • Recessive variants in the NDUFAF3 gene are linked to serious mitochondrial disorders that often lead to severe neurological issues and early death in affected infants.
  • A case study of a 10-year-old patient presents atypical symptoms including neurodevelopmental disorders, progressive exercise intolerance, and high blood lactate levels, identified through advanced genetic analysis revealing specific pathogenic variants in NDUFAF3.
  • Investigations into mitochondrial function showed reduced complex I activity and unusual findings in mitochondrial complex assembly, contributing important new insights into the complexities of NDUFAF3-related mitochondrial diseases and highlighting the variability in patient symptoms.
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Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities.

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Purpose: The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A.

Methods: Clinical, genomic, and functional studies using subject-derived fibroblasts and a heterologous cellular system were performed.

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  • De novo variants contribute significantly to neurodevelopmental disorders (NDDs), but due to their rarity, understanding the full range of symptoms and genetic variations linked to specific genes like KDM6B poses a challenge.
  • The study of 85 individuals with KDM6B variants reveals that cognitive deficits are common, while features like coarse facies and skeletal issues are rare, indicating that existing descriptions may be misleading.
  • Through innovative testing methods and studies on Drosophila, the researchers highlight the critical role of KDM6B in cognitive function and the importance of international collaboration for accurate diagnosis of rare disorders.
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Purpose: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.

Methods: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.

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We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in (). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects.

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  • Superoxide dismutase-1 (SOD1) is an important antioxidant enzyme, and mutations in its gene can lead to amyotrophic lateral sclerosis (ALS) by causing toxic protein aggregation.
  • Researchers studied eight children with a specific mutation (p.C112Wfs*11) that resulted in SOD1 deficiency, finding that they experienced progressive motor neuron dysfunction and brain atrophy starting around 8 months of age.
  • Despite motor system deterioration, other organs showed normal integrity and resilience, indicating a unique vulnerability of the motor system to changes in SOD1 function.
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  • Protein lipoylation is crucial for cell metabolism, with the H-protein (GCSH) playing a key role in this process for important enzymes and one-carbon metabolism.
  • A study of six patients with pathogenic variants in GCSH showed a range of clinical issues, from severe neonatal encephalopathy to milder developmental delays and movement disorders.
  • Functional analyses revealed that most mutations led to reduced mitochondrial activity and metabolic deficiencies, highlighting the importance of understanding these variants to guide treatment options.
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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.

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Background: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics.

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PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2.

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MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants.

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Voltage-gated calcium (CaV) channels form three subfamilies (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4.

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