Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants.

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials.

International consensus recommendations on the diagnostic work-up for malformations of cortical development.

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management.

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

Objective: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders.

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures.

De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome.

A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration.

The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH).

Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features.

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2.

Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes.

Copy number variants at chromosome 17q12 have been associated with a spectrum of phenotypes. Deletions of 17q12 are well described and associated with maturity onset diabetes of the young type 5 (MODY5) and cystic renal disease (HNF1β) as well as cognitive impairment and seizures. Duplication of 17q12 is emerging as a new genetic syndrome, associated with learning disability, seizures, and behavioral problems.

Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.

The gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in have been reported to cause a range of brain malformations.

Tubulin genes and malformations of cortical development.

A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation.

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with constitutive variants.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous variants. Here we have undertaken a detailed clinical study of 55 individuals with variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations.

Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals.

Loss of function mutations in CTNNB1 have been reported in individuals with intellectual disability [MIM #615075] associated with peripheral spasticity, microcephaly and central hypotonia, suggesting a recognisable phenotype associated with haploinsufficiency for this gene. Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified eleven further individuals with de novo loss of function mutations in CTNNB1. Here we report detailed phenotypic information on ten of these.

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.

Background: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy.

Methods: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein.

A rare example of germ-line chromothripsis resulting in large genomic imbalance.

Chromothripsis is a recently described 'chromosome catastrophe' phenomenon in which multiple genomic rearrangements are generated in a single catastrophic event. Chromothripsis has most frequently been associated with cancer, but there have also been rare reports of chromothripsis in patients with developmental disorders and congenital anomalies. In contrast to the massive DNA loss that often accompanies chromothripsis in cancer, only minimal DNA loss has been reported in the majority of cases of chromothripsis that have occurred in the germ line.

Diverse phenotypic consequences of mutations affecting the C-terminus of FLNA.

Unlabelled: Filamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C-terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein.

Further delineation of the KAT6B molecular and phenotypic spectrum.

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness.

We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology.

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows.