Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients.

Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.

Case Report of Pediatric HPCA-Associated Dystonia: Analysis of Ca and K Channel Dynamics and Experience With Pallidal Deep Brain Stimulation.

Background: Biallelic pathogenic variants in the HPCA gene cause HPCA-associated dystonia (DYT-HPCA), a rare autosomal recessive disorder characterized by generalized dystonia and complex motor symptoms. HPCA encodes hippocalcin, a Ca sensor that modulates neuronal activity through K channel activation. Here, we describe the clinical and molecular features of two children with novel HPCA variants and assess the impact of deep brain stimulation (DBS) (globus pallidus internus [Gpi]-DBS) on their movement disorders.

Loss of ANK3 Function Causes a Recessive Neurodevelopmental Disorder with Cerebellar Ataxia.

Background: ANK3 encodes ankyrin-G, a key scaffolding protein essential for neuronal function. While both monoallelic and biallelic ANK3 variants have been linked to neurodevelopmental disorders (NDDs), existing evidence for their pathogenicity and clinical correlation remains limited and heterogeneous.

Objective: To delineate the clinical features associated with biallelic ANK3 predicted loss-of-function (pLOF) variants.

Recessive Loss of PI4K2A Function Causes a Developmental and Epileptic Dyskinetic Encephalopathy with Prominent Orolingual Dyskinesia.

Background: Biallelic loss-of-function variants in PI4K2A have been associated with a neurodevelopmental disorder characterized by seizures and movement disorders, including orofacial dyskinesia. However, only 4 cases have been reported. Orolingual dyskinesia-defined as involuntary movements of the mouth and tongue-is observed in various pediatric neurodevelopmental disorders (NDD) but remains under-recognized.

Biallelic Truncating Variants in SCN3B Encoding Nav Channel Subunit β3 Lead to Neurodevelopmental Phenotype with and without Epilepsy and Ataxia.

SCN3B encodes the β3 auxiliary subunit, essential for voltage-gated Na (Nav) channel trafficking and gating. Although SCN3B has been associated with cardiac disorders, a link with neurodevelopmental disorders (NDD) has not been established. Using a genotype-first approach, we identified homozygous truncating variants (c.

variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.

encodes a subunit shared by the BLOC-1 and BORC hetero-octameric complexes that regulate various endolysosomal processes. Here, we report the identification of seven distinct variants in in eleven individuals from seven independent families presenting with early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination. A subset of the affected individuals also have features of hypopigmentation and ocular albinism that are similar, although milder, than those of individuals with BLOC-1-related Hermansky-Pudlak syndrome.

A programmed decline in ribosome levels governs human early neurodevelopment.

Many neurodevelopmental defects are linked to genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remains unclear. Here we describe variants in the ribosome biogenesis factor AIRIM/C1orf109 that are primarily associated with neurodevelopmental disorders.

Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series.

Background: The reasons why some individuals have severe neuropathy following an infection are not known. Through the agnostic screening of children with acute axonal neuropathy after an infection, we identified several families with biallelic variants in RCC1. We aimed to describe the clinical phenotype of these patients, and the molecular and cellular pathology associated with the genetic variants identified in these families.

Domain specific phenotypic expansion associated with variants in .

Purpose: While heterozygous missense variants in the microtubule-binding GAR domain of Microtubule-actin cross-linking factor 1 () cause Lissencephaly 9 with Complex Brainstem Malformations [MIM #618325], the phenotypic impact of variants outside this domain remains unclear.

Methods: Through collaborative efforts, we assembled a cohort of 10 affected individuals from 8 unrelated families with either biallelic or monoallelic non-GAR domain variants who exhibit partially overlapping yet unique phenotypic traits. Combined with previously reported cases, we analyzed genotype and phenotype data from 29 individuals using Human Phenotype Ontology (HPO)-based unsupervised hierarchical clustering.

Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis.

Background: Very long chain fatty acids (VLCFAs) are an integral component of myelin and the epidermal water barrier. Variants in genes encoding enzymes responsible for catalyzing the first and rate limiting step in the production of VLCFAs, elongation of VLCFAs (ELOVLs), underlie a novel group of metabolic disorders.

Objectives: The goal was to describe the clinical phenotype and disturbance in VLCFA metabolism associated with variants in the ELOV1 gene.

ELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy.

Purpose: Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability.

Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy.

Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing.

Early-Onset Movement Disorder Syndrome Caused by Biallelic Variants in PDE1B Encoding Phosphodiesterase 1B.

Background: Breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in basal ganglia cells through hydrolysis of diesteric bonds, primarily by PDE10A and PDE1B, is essential for normal human movement. While biallelic loss-of-function variants in PDE10A are known to cause hyperkinetic movement disorders, the role of PDE1B in human disease has not been characterized.

Objectives: We aimed to define the phenotypic and molecular characteristics of a novel autosomal recessive disorder caused by biallelic PDE1B variants.

Combinatorial transcriptional regulation establishes subtype-appropriate synaptic properties in auditory neurons.

Neurons develop diverse synapses that vary in content, morphology, and size. Although transcriptional regulators of neurotransmitter identity are known, it remains unclear how synaptic features are patterned among neuronal subtypes. In the auditory system, glutamatergic synaptic properties vary across three spiral ganglion neuron (SGN) subtypes that collectively encode sound.

HCN2-Associated Neurodevelopmental Disorders: Data from Patients and Xenopus Cell Models.

Objective: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in HCN2, encoding for the hyperpolarization-activated cyclic nucleotide (HCN) gated channel 2.

Methods: GeneMatcher facilitated the recruitment of 21 individuals with HCN2 variants from 15 unrelated families, carrying HCN2 variants. In vitro functional studies were performed by electrophysiology with Xenopus laevis oocytes and membrane trafficking was investigated in HEK cells by confocal imaging.

Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.

Monoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture of LGI1-ADAM22/23 pathway-related diseases remains incompletely understood.

Biallelic loss-of-function variants in ZNF142 are associated with a robust DNA methylation signature affecting a limited number of genomic loci.

Biallelic inactivating variants in ZNF142 underlie a clinically variable neurodevelopmental disorder. ZNF142 is a zinc-finger transcription factor with potential roles on chromatin organization, implying a possible association of ZNF142 loss of function with perturbed genome-wide DNA methylation (DNAm) pattern. We performed EPIC array-based methylation profiling of peripheral blood-derived DNA samples from 27 individuals with biallelic ZNF142 inactivating variants, together with 6 heterozygous carriers and 40 controls.

Pathogenic variants in Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction.

encodes a subunit of the BLOC-one-related complex (BORC), which is known to mediate the kinesin-dependent anterograde movement of lysosomes. Using whole-exome sequencing, we identified 12 cases from seven families carrying bi-allelic variants, including four loss-of-function and two missense variants. Carriers of homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy.

Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.

Defects in DNA single-strand break repair are associated with neurodevelopmental and neurodegenerative disorders. One such disorder is that resulting from mutations in XRCC1, a scaffold protein that plays a central role in DNA single-strand base repair. XRCC1 is recruited at sites of single-strand breaks by PARP1, a protein that detects and is activated by such breaks and is negatively regulated by XRCC1 to prevent excessive PARP binding and activity.

Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin.

DNA double strand break repair (DSBR) represents a fundamental process required to maintain genome stability and prevent the onset of disease. Whilst cell cycle phase and the chromatin context largely dictate which repair pathway is utilised to restore damaged DNA, it has been recently shown that nuclear actin filaments play a major role in clustering DNA breaks to facilitate DSBR by homologous recombination (HR). However, the mechanism with which nuclear actin and the different actin nucleating factors regulate HR is unclear.

SLK is mutated in individuals with a neurodevelopmental disorder.

Background: Key to neuronal cell polarization and maturation is proper cytoskeletal organization and function that endows the bipolar neuronal cell with mature dendrites, axons, and functional synapses. Ste20-like kinase (SLK) has been shown to have various cytoskeletal roles. SLK regulates the polarity of microtubules, and its deficiency in the developing murine cortex leads to major defects including impaired development of the distal dendritic tree.

Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.

Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic conditions caused by defects in glycoprotein and glycolipid glycan assembly and remodeling, a fundamental molecular process with wide-ranging biological roles. Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from ten unrelated families of various ethnic backgrounds as a cause of a distinctive CDG of variable severity. The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder.

The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants in tRNA-modification enzymes have been implicated in a wide range of human neurodevelopmental and neurological disorders. However, the molecular basis for many of these disorders remains unknown.

Uncovering the genetic architecture of inherited retinal disease in a consanguineous Iranian cohort.

An integrated approach combining whole exome sequencing (WES) and autozygosity mapping was used to molecularly diagnose inherited retinal disease (IRD) in 192 unrelated Iranian families, 76.1% of which originate from a consanguineous background. Data analysis was performed using an in-house pipeline to detect single-nucleotide variants (SNVs), small insertions and deletions, copy number variants (CNVs) and runs of homozygosity (ROHs).

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits.