Publications by authors named "Alexander Stegmann"

Article Synopsis
  • - 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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Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca/calmodulin-dependent protein kinase II.

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Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy.

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FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems.

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Article Synopsis
  • Genetic laboratories currently use diverse workflows to diagnose hereditary and congenital diseases, and this study assesses the potential of genome sequencing (GS) to streamline these processes.
  • The researchers tested GS on 1,000 cases with known genetic variants to evaluate its effectiveness compared to existing methods, finding that GS detected 95% of variants across different categories.
  • The results suggest that adopting a GS-first approach could replace multiple workflows in around 85% of clinical cases, allowing for more efficient and comprehensive diagnostics for rare genetic diseases.
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Objective: The chromosome region 22q11.2 is highly susceptible to genomic rearrangements. It has become clear that genomic instability extends distally to the commonly deleted/duplicated region (Low Copy Repeats [LCR] A-D) and that a clear difference exists between the phenotypic presentation of patients with rearrangements in the common region versus that in the distal region (LCR D-H), particularly with respect to developmental and somatic issues.

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Article Synopsis
  • Short-read sequencing can struggle to analyze duplicated genomic regions, making it hard to identify many genetic variants in standard studies.
  • The new method, Chameleolyser, improves the identification of single nucleotide variants, small insertions/deletions, and other genetic events in these complex regions using whole-exome sequencing data.
  • In testing with 41,755 exome samples, the method discovered over 2.5 million rare variants and validated a significant percentage of them, providing molecular diagnoses for several previously undiagnosed patients.
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Article Synopsis
  • 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: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.

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Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1.

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Collapsin response mediator proteins (CRMPs) are key for brain development and function. Here, we link CRMP1 to a neurodevelopmental disorder. We report heterozygous de novo variants in the gene in three unrelated individuals with muscular hypotonia, intellectual disability, and/or autism spectrum disorder.

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Purpose: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome.

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Article Synopsis
  • Embryonic development relies on precise DNA processes, and mutations in repair genes can cause neurodevelopmental disorders with symptoms like microcephaly and short stature.
  • Researchers identified genetic variants in SLF2 and SMC5 from the RAD18-SLF1/2-SMC5/6 pathway in patients with developmental issues, including abnormal chromosomes and anemia.
  • The new disorder, named Atelís Syndrome, demonstrates heightened replication stress and difficulties with specific DNA structures, emphasizing the crucial role of the SLF2-SMC5/6 pathway in preserving genome stability.
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Article Synopsis
  • - The study focuses on identifying disease-associated genes on chromosome X, which is difficult due to its unique inheritance patterns.
  • - Researchers found a notable prevalence of genes related to cognitive functions and seizures on chromosome X and identified 127 genes that may be associated with known disorders.
  • - Utilizing machine learning, the team classified 247 genes as likely disease-associated and highlighted specific damaging variants in CDK16 and TRPC5 linked to intellectual disabilities and autism spectrum disorders.
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Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.

Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases.

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Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios.

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Article Synopsis
  • Germline loss-of-function variants in the CTNNB1 gene are linked to neurodevelopmental disorders that include spastic diplegia and visual issues, making them a common genetic cause of cerebral palsy (CP).
  • A study analyzed genetic data from 404 individuals with pathogenic CTNNB1 variants, including newly detailed phenotypes for 52 cases, to explore how these variants relate to CP and other traits.
  • Findings showed that individuals with CTNNB1 variants exhibited similar clinical features, suggesting that CP is part of the neurodevelopmental disorder spectrum rather than a separate condition; two specific variants were found to disrupt WNT signaling processes.
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Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants.

Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome.

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We identified six novel de novo human variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. 101: 65-74, 2017).

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Purpose: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.

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Calcium (Ca) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca pumps that participate in the regulation of intracellular free Ca. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay.

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Objective: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy.

Methods: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment.

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Article Synopsis
  • The study investigated the clinical characteristics and genetic variations associated with the DHX30-related neurodevelopmental disorder, especially focusing on new missense variants in the gene.
  • Researchers collected clinical and genetic data from affected individuals via social media, collaboration networks, and analyzed the effects of these variants on cellular functions and development using various experimental models, including zebrafish.
  • Findings revealed that individuals with missense variants presented with severe developmental issues, while those with variants leading to milder haploinsufficiency showed less severe symptoms, suggesting the presence of two distinct clinical subtypes based on the type and location of the genetic variants.
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