Publications by authors named "Hartmut Engels"

Article Synopsis
  • * 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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PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance.

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  • Fibroblast growth factor 10 (FGF10) is crucial for lung development and can lead to serious conditions like LADD syndrome when mutated.
  • This study examines four children with complications from childhood Interstitial Lung Disease (chILD) linked to heterozygous FGF10 mutations, highlighting their severe respiratory issues.
  • Findings indicate that even without notable syndromic features, FGF10-related disorders should be considered in children facing postnatal respiratory distress, as they may lead to severe outcomes, including pulmonary hypertension and lung fibrosis.
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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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Article Synopsis
  • - DNA methylation classifiers, known as episignatures, help assess the pathogenicity of uncertain genetic variants, but they've been limited in sensitivity for variants with weaker effects or in mosaic states.
  • - The study improved episignatures in three ways: reducing their length for efficiency, increasing their sensitivity by 30% through re-training techniques, and confirming links between DNA methylation changes and patient characteristics like age at onset of dystonia.
  • - The enhanced classifiers can now detect subtle mosaic cases that were previously missed and correct inaccurate interpretations of mosaicism, showcasing their potential for better genetic analysis.
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BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations.

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encodes the Protein-Tyrosine Phosphatase, Receptor-Type, F Polypeptide-Interacting Protein Alpha-3 (PPFIA3), which is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family involved in synaptic vesicle transport and presynaptic active zone assembly. The protein structure and function are well conserved in both invertebrates and vertebrates, but human diseases related to PPFIA3 dysfunction are not yet known. Here, we report 14 individuals with rare mono-allelic variants presenting with features including developmental delay, intellectual disability, hypotonia, autism, and epilepsy.

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Next-generation phenotyping (NGP) is an application of advanced methods of computer vision on medical imaging data such as portrait photos of individuals with rare disorders. NGP on portraits results in gestalt scores that can be used for the selection of appropriate genetic tests, and for the interpretation of the molecular data. Here, we report on an exceptional case of a young girl that was presented at the age of 8 and 15 and enrolled in NGP diagnostics on the latter occasion.

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Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this 'supervised' approach means that diagnoses are only possible if the disorder was part of the training set.

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Article Synopsis
  • SPTBN1 gene encodes βII-spectrin, crucial for forming networks at plasma membranes, and its deficiency in mice leads to significant neurodevelopmental issues.
  • Heterozygous variants of SPTBN1 were identified in 29 individuals exhibiting a range of developmental challenges, including intellectual disabilities, language delays, and autistic features.
  • These variants weaken βII-spectrin stability and disrupt cellular organization, establishing SPTBN1 as a key contributor to certain neurodevelopmental syndromes.
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Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19).

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Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.

Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants.

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Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

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  • Mutations in the MYT1L gene and microdeletions in chromosome band 2p25.3 are linked to intellectual disabilities, obesity, and behavioral issues, suggesting that MYT1L is a key gene in the 2p25.3 deletion syndrome.
  • *Recent research identified nine new individuals with MYT1L mutations, raising the total number of documented cases to 51, with a notable proportion having simple mutations rather than larger deletions.
  • *A comparison between individuals with MYT1L mutations and those with larger deletions revealed differences in obesity rates and short stature, reinforcing the importance of MYT1L haploinsufficiency in the disorder's symptoms and contributing to a better understanding of the
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A male patient with mosaic paternal uniparental diploidy (PUD) is presented. After birth, the patient presented with hypoglycemia, hemihypertrophy, umbilical hernia, and hepatomegaly. Afterward pancreatic hypertrophy, liver hemangiomas, and cysts were detected sonographically.

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A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.

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Our findings extend the phenotypic spectrum of Cat eye syndrome, a disorder with wide clinical variability. The potentially life-threatening complications of congenital diaphragmatic hernia should be considered in genetic counseling and prenatal diagnostic.

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Article Synopsis
  • * Variants in NALCN and its associated protein UNC80 can lead to conditions like infantile hypotonia and developmental delays, with specific variants causing distinct clinical features.
  • * This study provides new clinical data on individuals with NALCN and UNC80 variants, enhancing understanding of related phenotypes and variability to aid in family counseling.
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Congenital diaphragmatic hernia (CDH) is a rare defect of the diaphragm commonly associated with high morbidity and mortality due to lung hypoplasia and pulmonary hypertension. Although in 70% of patients the etiology of a CDH remains unknown, a multitude of causative chromosomal aberrations has been identified. We describe the first case of isolated 11p15 duplication with CDH.

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Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%).

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  • Intellectual disability (ID) affects about 1.5-2% of the population, but the genetic causes are often unknown; whole exome sequencing (WES) has helped identify new gene defects linked to sporadic ID cases, particularly de novo mutations.
  • This study discusses two unrelated boys with ID and similar clinical features, both found to have harmful gene mutations in FBXO11 through WES.
  • The findings confirm that de novo mutations in FBXO11 can lead to ID and highlight related symptoms such as microcephaly and behavioral issues, which helps in understanding the clinical implications of this genetic variant.
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For a large number of individuals with intellectual disability (ID), the molecular basis of the disorder is still unknown. However, whole-exome sequencing (WES) is providing more and more insights into the genetic landscape of ID. In the present study, we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients with ID from two unrelated families.

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