Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels

Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome

Ellis van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with three affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the three affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a frameshift change (p.Val141*) in two siblings with EvC from a second family, while a newborn with a more severe phenotype carried two DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function

Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature

Background: KBG syndrome is caused by haploinsufficiency of ANKRD11and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects ofANKRD11variants in skeletal and brain development

Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnosesparticularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD

Atrioventricular canal defect in patients with RASopathies

Congenital heart defects affect 60-85% of patients with RASopathies. We analysed the clinical and molecular characteristics of atrioventricular canal defect in patients with mutations affecting genes coding for proteins with role in the RAS/MAPK pathway. Between 2002 and 2011, 101 patients with cardiac defect and a molecularly confirmed RASopathy were collected. Congenital heart defects within the spectrum of complete or partial (including cleft mitral valve) atrioventricular canal defect were diagnosed in 8/101 (8%) patients, including seven with a PTPN11 gene mutation, and one single subject with a RAF1 gene mutation. The only recurrent mutation was the missense PTPN11 c.124 A>G change (T42A) in PTPN11. Partial atrioventricular canal defect was found in six cases, complete in one, cleft mitral valve in one. In four subjects the defect was associated with other cardiac defects, including subvalvular aortic stenosis, mitral valve anomaly, pulmonary valve stenosis and hypertrophic cardiomyopathy. Maternal segregation of PTPN11 and RAF1 gene mutations occurred in two and one patients, respectively. Congenital heart defects in the affected relatives were discordant in the families with PTPN11 mutations, and concordant in that with RAF1 mutation. In conclusion, our data confirm previous reports indicating that atrioventricular canal defect represents a relatively common feature in Noonan syndrome. Among RASopathies, atrioventricular canal defect was observed to occur with higher prevalence among subjects with PTPN11 mutations, even though this association was not significant possibly because of low statistical power. Familial segregation of atrioventricular canal defect should be considered in the genetic counselling of families with RASopathies. © 2013 Macmillan Publishers Limited. All rights reserved

RDDR: a dysmorphology diagnostic network for newborns in central Italy

In 2011, the RDDR network was developed in central Italy to provide support in the diagnosis of dysmorphic newborns. RDDR has been developed as an online electronic system that currently links 20 neonatology centres in central Italy, representing the submitting nodes that transmit patient clinical histories and the relevant photographical documentation to the software, which is password-protected. Accepted cases appropriate for the RDDR are reviewed by the RDDR's dysmorphology experts who, through a forum section, provide diagnostic suggestions and recommendations for further investigation and patient management. Their remarks are summarised in clinical expert reports and sent to the submitting nodes. The results of the first 22 submitted cases are reviewed in this paper. The RDDR was developed on the basis of a related European tool, Dyscerne, a network of centres of expertise for dysmorphology

GRIA3 missense mutation is cause of an x-linked developmental and epileptic encephalopathy

Purpose: GRIA3, encoding subunit 3 of glutamate ionotropic AMPA receptor, is associated with X-linked intel-lectual disability (ID), dysmorphic features, and non-syndromic epilepsy. We aimed to characterize electroclinical features of patients with GRIA3 variants.Methods: We report a patient carrying a hemizygous missense variant c.2359 G > A (p.Glu787Lys) inGRIA3 gene. Following a literature search, we also reviewed clinical, electrophysiological, radiological, and genetic features of 19 patients with GRIA3 mutations.Results: This 26-month-old boy had developmental delay, early onset refractory myoclonic epilepsy, and non convulsive refractory status epilepticus. In published reports, epilepsy was in 6 of 19 patients carrying different genotypes, though epilepsy and electroencephalogram features were not completely defined. Out of the 6 patients, one presented with generalized tonic-clonic seizures, two with myoclonic and clonic events (one also presented with epileptic spasms), and one with atypical absences and myoclonic jerks. Information on type of epilepsy was unavailable for 3 cases. Epilepsy onset was early in life and there was potential tendency for myoclonic/clonic events. The epilepsy was difficult to treat and prognosis is poor. Severity of ID ranged from mild to severe and was variably associated with bipolar affective disorder and autistic spectrum disorders. Other neurological features included hypotonia, asthenic body habitus with poor muscle bulk, and hyporeflexia.Conclusion: Our report expands knowledge on the electro-clinical and molecular spectrum of GRIA3 variants. Larger investigations will better define the prevalence of epilepsy, the epileptic phenotype, and syndromic features underlying GRIA3 variants

Ectodermal Dysplasia-Syndactyly Syndrome with Toe-Only Minimal Syndactyly Due to a Novel Mutation in NECTIN4: A Case Report and Literature Review

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the adherens junction component nectin-4. Nine EDSS1 cases have been described to date. We report a 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in the NECTIN4 gene. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. Our case, which represents the first report of a NECTIN4 mutation with toe-only minimal syndactyly, expands the phenotypic and molecular spectrum of EDSS1

MED13 mutation: A novel cause of developmental and epileptic encephalopathy with infantile spasms

Purpose: Mutations in the MED13 gene are reported in the literature in association with clinically variable, neurodevelopmental disorders, which are characterized by mild-to-severe intellectual disability, autism spectrum disorder, attention deficit/hyperactivity disorder, epilepsy, ocular or skeletal abnormalities, congenital cardiac defects, and facial dysmorphisms. Here, we report a patient with an epileptic phenotype carrying a novel missense mutation characterized by developmental and epileptic encephalopathy with infantile spasms.Methods: Through trio-based WES, we identified a novel de novo heterozygous missense variant c.2501A>G in the MED13 gene. We reviewed all medical charts of the present patient and reviewed all previously reported cases with pathogenic variants of MED13. Results: This study involves a 24-month-old boy with epilepsy onset at the age of 3 months with drug-resistant focal seizures followed by infantile spasms at the age of 10 months. He had a severe, developmental delay along with microcephaly and dysmorphic features. From a literature review, it emerged that epilepsy is described in only one out of nineteen of previously reported patients with a phenotype of generalized, drug-resistant epilepsy with myoclonic-atonic seizures. Microcephaly, developmental delay, hypotonia, corpus callosum abnormalities, deafness, and retinal atrophy were common features in the previously described cases.Conclusion: This case expands the genetic landscape of infantile spasms as well as the phenotype of MED13-related disorders adding the electroclinical features of early-onset developmental and epileptic encephalopathy with infantile spasms to the previously described, generalized epilepsy with myoclonic-atonic seizures