Exploring the Frontier: The Human Microbiome's Role in Rare Childhood Neurological Diseases and Epilepsy.

Emerging research into the human microbiome, an intricate ecosystem of microorganisms residing in and on our bodies, reveals that it plays a pivotal role in maintaining our health, highlighting the potential for microbiome-based interventions to prevent, diagnose, treat, and manage a myriad of diseases. The objective of this review is to highlight the importance of microbiome studies in enhancing our understanding of rare genetic epilepsy and related neurological disorders. Studies suggest that the gut microbiome, acting through the gut-brain axis, impacts the development and severity of epileptic conditions in children.

Expanded carrier screening for inherited genetic disease using exome and genome sequencing.

The goal of this study was to assess the feasibility of using exome (ES) and genome sequencing (GS) in guiding preconception genetic screening (PCGS) for couples who are planning to conceive by creating a workflow for identifying risk alleles for autosomal recessive (AR) and X-linked (XL) disorders without the constraints of a predetermined, targeted gene panel. There were several limitations and challenges related to reporting and the technical aspects of ES and GS, which are listed in the discussion. We selected 150 couples from a cohort of families (trios) enrolled in a research protocol where the goal was to define the genetic etiology of disease in an affected child.

Snyder-Robinson syndrome presenting with learning disability, epilepsy, and osteoporosis: a novel gene variant.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder characterized by a collection of clinical features including mild to severe intellectual disability, hypertonia, marfanoid habitus, facial asymmetry, osteoporosis, developmental delay and seizures. Whole genome sequencing (WGS) identified a mutation in the spermine synthase () gene (c.746 A>G, p.

FGF12 copy number variant associated with epileptic encephalopathy.

FGF12 related epilepsy presents with variable phenotypes. We report another patient with a duplication involving the FGF12 gene who presented similar to other published cases having normal early development and responded to phenytoin.

Inherited CSNK2A1 variants in families with Okur-Chung neurodevelopmental syndrome.

Pedigree showing the autosomal dominant inheritance pattern of CSNK21 variants in families presenting with OCNDS. (A) Maternal inheritance to two daughters in Family 1, (B) Paternal inheritance to a daughter in Family 2, and (C) Maternal inheritance to two sons in Family 3.

Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc).

Gain-of-function variants in the ion channel gene underlie a spectrum of neurodevelopmental disorders.

TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function .

Progressive bilateral nuclear cataracts associated with cerebellar-facial-dental syndrome: case report, literature review, and identification of a new genetic variant.

Cerebellar-facial-dental syndrome (CFDS) is a newly described autosomal recessive genetic disorder characterized by mutations in the BRF1 gene. CFDS is clinically associated with dysmorphic facial features and cerebellar hypoplasia. We report visually significant progressive bilateral nuclear cataracts in a child with CFDS and identify a new causative genetic variant.

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.

Purpose: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.

Methods: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.

Results: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS.

Congenital myasthenic syndrome caused by a frameshift insertion mutation in .

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 () gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.

Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed.

Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction.

Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia.

We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.

A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41-q42 deletion phenotype.

Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28.

Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results.

Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly.

Exploring genome-wide DNA methylation patterns in Aicardi syndrome.

Aim: To explore differential DNA methylation (DNAm) in Aicardi syndrome (AIC), a severe neurodevelopmental disorder with largely unknown etiology.

Patients & Methods: We characterized DNAm in AIC female patients and parents using the Illumina 450 K array. Differential DNAm was assessed using the local outlier factor algorithm, and results were validated via qPCR in a larger set of AIC female patients, parents and unrelated young female controls.

Case Report: Novel mutations in are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability.

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the gene segregating within this family (c.

A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4).

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach.

Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via β-oxidation (He et al. 2007).

A de novo missense mutation in ZMYND11 is associated with global developmental delay, seizures, and hypotonia.

Recently, mutations in the zinc finger MYND-type containing 11 (ZMYND11) gene were identified in patients with autism spectrum disorders, intellectual disability, aggression, and complex neuropsychiatric features, supporting that this gene is implicated in 10p15.3 microdeletion syndrome. We report a novel de novo variant in the ZMYND11 gene (p.

Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

Objective: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.

Methods: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.