CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is ...one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.
Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to ...neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.
Variants in the chromodomain helicase DNA‐binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the ...causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate‐to‐severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non‐ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex‐dependent penetrance of CHD8 PTVs in humans.
Variants in the chromodomain helicase DNA‐binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASD) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (DD/ID, 81%), autism spectrum disorders (ASD, 84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate‐to‐severe intellectual disability, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were also non‐ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex‐dependent penetrance of CHD8 PTVs in humans.
Musculocontractural Ehlers-Danlos syndrome (mcEDS) is an autosomal recessive condition characterized by distinct craniofacial features, multisystem congenital malformations and progressive fragility ...of connective tissues. It is caused by pathogenic variants in CHST14 and DSE genes. There are three reports of pathogenic variants in DSE in four mcEDS patients. In this study we provide clinical and molecular presentation of two new patients with DSE related mcEDS.
Analysing clinical exome data, a homozygous pathogenic DSE variant, c.1150_1157del p.(Pro384Trpfs*9), was identified in a 32 year old man with bilateral congenital talipes equinovarus, characteristic facial features, myopia, hyperextensible skin at the elbows, significant palmar wrinkling, bilateral inguinal hernias and chronic leg, back and joint pain. Electron microscopical examination of skin biopsy showed changes consistent with mild compensatory elastic fibre hypertrophy and mildly loose collagen bundles.
The variant is predicted to result in a frameshift and introduction of a premature termination codon in the final exon of the DSE gene, anticipated to lead to the loss of approximately 60% of the normal reading frame. The second patient has a phenotype consistent with previously reported cases of DSE associated musculocontractural EDS. A novel homozygous missense DSE variant of uncertain clinical significance was detected.
This case study further delineates the DSE associated mcEDS phenotype and illustrates absence of major cutaneous, cardiovascular, renal and respiratory features, which supports previous suggestions that patients with DSE associated mcEDS present with a milder phenotype compared to those with CHST14 mutations.
Summary
Objective
The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this ...phenotype is PCDH19, an X‐linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in‐frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug‐resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation.
Method
Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained.
Results
Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases.
Significance
Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.
Clinical and genetic aspects of KBG syndrome Low, Karen; Ashraf, Tazeen; Canham, Natalie ...
American journal of medical genetics. Part A,
November 2016, Letnik:
170A, Številka:
11
Journal Article
CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated ...patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
Recent evidence has emerged linking mutations in
to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with
mutations.
Patients were ...investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.
Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.
These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the
gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.
Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense ...mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.
•One third of Bainbridge-Ropers patients have seizures.•Epilepsy features of 3 patients with Bainbridge-Ropers syndrome are presented.•Childhood-onset generalized tonic-clonic and/or absence seizures ...are typical.•EEG may show generalized spike-wave, OIRDA or photoparoxysmal response.
Bainbridge-Ropers syndrome is a genetic syndrome caused by heterozygous loss-of-function pathogenic variants in ASXL3, which encodes a protein involved in transcriptional regulation. Affected individuals have multiple abnormalities including developmental impairment, hypotonia and characteristic facial features. Seizures are reported in approximately a third of cases; however, the epileptology has not been thoroughly studied. We identified three patients with pathogenic ASXL3 variants and seizures at Austin Health and in the DECIPHER database. These three patients had novel de novo ASXL3 pathogenic variants, two with truncation variants and one with a splice site variant. All three had childhood-onset generalized epilepsy with generalized tonic-clonic seizures, with one also having atypical absence seizures. We also reviewed available clinical data on five published patients with Bainbridge-Ropers syndrome and seizures. Of the five previously published patients, three also had generalized tonic-clonic seizures, one of whom also had possible absence seizures; a fourth patient had absence seizures and possible focal seizures. EEG typically showed features consistent with generalized epilepsy including generalized spike-wave, photoparoxysmal response, and occipital intermittent rhythmic epileptiform activity. Bainbridge-Ropers syndrome is associated with childhood-onset generalized epilepsy with generalized tonic-clonic seizures and/or atypical absence seizures.
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