CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability.

Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis, and in silico modeling. We observed an altered network synchronization in CACNA1A+/- networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2-lacking AMPA receptors.

Ameliorated cellular hallmarks of myotonic dystrophy in hybrid myotubes from patient and unaffected donor cells.

Background: Cell-based strategies are being explored as a therapeutic option for muscular dystrophies, using a variety of cell types from different origin and with different characteristics. Primary pericytes are multifunctional cells found in the capillary bed that exhibit stem cell-like and myogenic regenerative properties. This unique combination allows them to be applied systemically, presenting a promising opportunity for body-wide muscle regeneration.

Generation of induced pluripotent stem cell line (UCSFi001-A-77) carrying a biallelic frameshift variant in exon 4 of SGIP1 through CRISPR/Cas9.

SGIP1 encodes a protein Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1. It is involved in the regulation of clathrin-mediated endocytosis along with having a role in energy homeostasis in neuronal systems. We generated an isogenic human induced pluripotent stem cell (iPSC) line with a biallelic frameshift variant in SGIP1.

Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery.

Generation of induced pluripotent stem cell lines from two unrelated patients affected by intellectual disability carrying homozygous variants in SGIP1.

Intellectual disability (ID) is a diverse neurodevelopmental condition and almost half of the cases have a genetic etiology. SGIP1 acts as an endocytic protein that influences the signaling of receptors in neuronal systems related to energy homeostasis through its interaction with endophilins. This study focuses on the generation and characterization of induced pluripotent stem cells (iPSC) from two unrelated patients due to a frameshift variant (c.

SCN1A-deficient excitatory neuronal networks display mutation-specific phenotypes.

Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioural problems and developmental delay. Eighty per cent of patients with Dravet syndrome have a mutation in SCN1A, encoding Nav1.1.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs.

Genetic diagnostic approach to intellectual disability and multiple congenital anomalies in Indonesia.

Intellectual disability (ID) and multiple congenital anomalies (MCA) are major contributors to infant mortality, childhood morbidity, and long-term disability, with multifactorial aetiology including genetics. We aim to set a diagnostic approach for genetic evaluation of patients with ID and MCA, which can be applied efficiently with a good diagnostic rate in Indonesia or other low resources settings. Out of 131 ID cases, twenty-three individuals with ID/global developmental delay (GDD) and MCA were selected from two-steps of dysmorphology screening and evaluation.

A complex structural variant near causes X-linked split-hand/foot malformation.

Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development. Although several genes and contiguous gene syndromes are implicated in the monogenic etiology of isolated SHFM, the disorder remains genetically unexplained for many families and associated genetic loci.

Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes.

We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well-known syndromes: Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants.

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity.

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome.

Generation of induced pluripotent stem cell lines carrying monoallelic (UCSFi001-A-60) or biallelic (UCSFi001-A-61; UCSFi001-A-62) frameshift variants in CACNA1A using CRISPR/Cas9.

CACNA1A encodes a P/Q-type voltage-gated calcium channel. Heterozygous loss-of-function variants in this gene have been associated with episodic ataxia type 2. In this study, we used CRISPR/Cas9 to generate isogenic human induced pluripotent stem cell lines with a gene-dosage dependent deficiency of CACNA1A.

THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.

Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability.

The complexities of CACNA1A in clinical neurogenetics.

Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum.

Biallelic in-frame deletion of SOX4 is associated with developmental delay, hypotonia and intellectual disability.

Intellectual disability (ID) represents an extremely heterogeneous group of disorders, characterized by significant limitations in intellectual function and adaptive behavior. Among the monogenic causes, autosomal recessive genes (ARID) are responsible for more than 50% of ID. Here, we report a novel in-frame homozygous deletion variant [c.

Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures.

Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C () and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 () are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types.

Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations in vitro.

Micro-electrode arrays (MEAs) are increasingly used to characterize neuronal network activity of human induced pluripotent stem cell (hiPSC)-derived neurons. Despite their gain in popularity, MEA recordings from hiPSC-derived neuronal networks are not always used to their full potential in respect to experimental design, execution, and data analysis. Therefore, we benchmarked the robustness of MEA-derived neuronal activity patterns from ten healthy individual control lines, and uncover comparable network phenotypes.

Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders.

Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons.

Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation.

EDEM3 encodes a protein that converts ManGlcNAc isomer B to ManGlcNAc. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3.