Publications by authors named "Andres Moreno-De-Luca"

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15).

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Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of () in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly.

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Article Synopsis
  • Biallelic variants in the ZBTB11 gene are linked to a rare intellectual developmental disorder known as MRT69, which shows a variety of clinical symptoms.
  • The study focused on analyzing clinical and genetic traits of 29 individuals (ages 2-50) with these variants, finding diverse neurodevelopmental issues and complex movement disorders among the patients.
  • Results revealed that many patients had abnormal movements (like ataxia and dystonia) and cataracts, with one patient showing improvement from deep brain stimulation, contributing 13 new genetic variants to the understanding of ZBTB11-related disorders.
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Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is one of the most common reasons for paediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate congenital hydrocephalus risk gene; however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated congenital hydrocephalus (totalling 2697 parent-proband trios and 8091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, congenital hydrocephalus, developmental delay, dysmorphic features and other structural brain defects, including corpus callosum dysgenesis and white matter hypoplasia.

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Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys.

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Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC.

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Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome.

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Article Synopsis
  • Biallelic variants in the OGDHL gene, linked to various neurological disorders, were investigated to better understand their gene-disease relationship through a new patient cohort and various genetic analyses.
  • Researchers utilized global sequencing data and zebrafish models to explore the functional effects of these variants, revealing significant clinical variability among affected individuals.
  • Findings indicated that OGDHL is not a straightforward Mendelian gene due to the presence of alternative allele interactions and compensatory mechanisms with related genes, suggesting a more complex role in neurodevelopmental disorders.
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Importance: Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH).

Objective: To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH.

Data Sources: PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023.

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Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling.

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Importance: Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery. A few familial forms of congenital hydrocephalus (CH) have been identified, but the cause of most sporadic cases of CH remains elusive. Recent studies have implicated , a component of the B RG1- a ssociated factor (BAF) chromatin remodeling complex, as a candidate CH gene.

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Article Synopsis
  • The study focused on understanding vein of Galen malformations (VOGMs), which are severe congenital brain abnormalities, by analyzing the genetic data from 310 affected individuals and their families, as well as a large database of human cerebrovascular cells.
  • Researchers identified significant genetic mutations, particularly in the gene p120 RasGAP and the Ephrin receptor-B4, which play roles in limiting Ras activation and are key to VOGM development.
  • Experiments on mice with specific genetic alterations revealed that abnormal activation of signaling pathways in endothelial cells leads to developmental issues in blood vessel formation, providing insights into both the biology of VOGMs and potential clinical applications for treatment.
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Background: Hirayama disease, a cervical myelopathy characterized most commonly by a self-limiting atrophic weakness of the upper extremities, is a rare entity, scarcely reported in the literature. Diagnosis is made by spinal magnetic resonance imaging (MRI), which typically shows loss of normal cervical lordosis, anterior displacement of the cord during flexion, and a large epidural cervical fat pad. Treatment options include observation or cervical immobilization by collar or surgical decompression and fusion.

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  • Exome sequencing is recommended as a primary diagnostic tool for neurodevelopmental disorders, but is not typically included for cerebral palsy.* -
  • The study analyzed existing research to determine if the genetic testing yields for cerebral palsy are comparable to those of other neurodevelopmental disorders.* -
  • Out of 13 qualifying studies with over 2,600 participants, the overall diagnostic yield for cerebral palsy was found to be 31.1%, with higher rates in children compared to adults.*
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  • Advances in molecular diagnostics have shown that certain genetic variants linked to neurodegenerative diseases can also cause severe neurodevelopmental disorders when inherited in a biallelic manner.* -
  • The study focuses on TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5), revealing a range of clinical symptoms across a cohort of 57 individuals, including severe flexion contractures, developmental delays, and various motor issues.* -
  • The research identified a phenotypic spectrum from mild symptoms to severe disabilities, with a notable survival rate of 71% and a median mortality age of 1.2 months, mainly due to complications like respiratory failure.*
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Purpose: Recurrent 16p11.2 duplications produce a wide range of clinical outcomes with varying effects on cognition and social functioning. Family-based studies of copy number variants (CNVs) have revealed significant contributions of genomic background on variable expressivity.

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Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging.

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  • 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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Biallelic pathogenic variants in the genes encoding the dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle-eye-brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease-dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described.

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  • The study focuses on the significance of phosphatidylinositol 4-phosphate (PI4P) as a crucial lipid in organelle membranes, impacting various cellular processes, and highlights the role of four phosphatidylinositol 4-kinases (PI4K) in mammalian cells, particularly PI4KA and PI4K2A.
  • Researchers identified two patients with PI4K2A deficiency, linked to neurodevelopmental disorders (NDD) and severe brain malformations, using exome sequencing, and discovered a high mortality rate in affected individuals.
  • Cellular assays confirmed that mutations in PI4K2A negatively impact its function, establishing a connection between deficiencies in
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