13 research outputs found
HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein
HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.publishedVersio
New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (PÂ <Â 5Â ĂÂ 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms
Genetic aetiologies and phenotypic variations of childhood-onset epileptic encephalopathies and movement disorders
Abstract
Novel genetic aetiologies for epileptic encephalopathies and movement disorders have been discovered by using next-generation sequencing methods. The phenotypic and genotypic variability in these conditions is very wide.
The aim of this study was to discover novel genetic causes and phenotypes of childhood-onset drug-resistant epilepsy and epileptic or developmental encephalopathies that occur separately or together with movement disorders, and familial movement disorders. Furthermore, the use of whole-exome sequencing (WES) as a diagnostic tool in clinical practice was evaluated. Altogether, 12 children with undefined aetiology, who fulfilled the inclusion criteria, were included in the study.
GABRG2 gene was identified as a genetic cause of epileptic encephalopathies. Novel GABRG2-associated phenotypes included progressive neurodegeneration, epilepsy in infancy with migrating focal seizures, and autism spectrum disorder. New pathogenic variants, GABRG2 p.P282T and p.S306F, were discovered.
The pathogenic NACC1 variant caused focal epilepsy, developmental disability, bilateral cataracts, and dysautonomia. The novel phenotype associated with the NACC1 p.R298W variant included hyperkinetic movement disorder.
SAMD9L was found to be the genetic cause for the familial movement disorder. The phenotype associated with the novel SAMD9L p.I891T variant was very variable. Neuroradiological findings included cerebellar atrophy and periventricular white matter changes. After publication of these results, SAMD9L was reported to be one of the most common genetic aetiologies of childhood bone marrow failure and myelodysplastic syndrome.
The pathogenic homozygous MTR variant was found to cause early-onset epileptic encephalopathy that occurred together with movement disorder and haematological disturbances. Drug resistant seizures responded to cofactor and vitamin treatments.
Whole-exome sequencing for 10 patients with drug-resistant epilepsy or epileptic or developmental encephalopathy provided a genetic diagnosis for two patients (20%).
This study confirmed that, for epileptic encephalopathies and movement disorders in which the genetic causes and phenotypes are heterogeneous and sometimes treatable, WES is a useful tool for diagnostics and in the search for novel aetiologies, which might turn out to be more common than expected.TiivistelmÀ
Uusien sekvensointimenetelmien kÀyttöönotto on mahdollistanut epileptisten enkefalopatioiden ja liikehÀiriöiden uusien geneettisten syiden löytymisen. NÀissÀ sairausryhmissÀ geenien ja ilmiasujen vaihtelevuus on suurta.
Tutkimuksen tarkoituksena oli löytÀÀ uusia geneettisiÀ syitÀ ja ilmiasuja lapsuusiÀllÀ alkavissa vaikeahoitoisissa epilepsioissa ja epileptisissÀ tai kehityksellisissÀ joko itsenÀisesti tai yhdessÀ liikehÀiriön kanssa esiintyvissÀ enkefalopatioissa sekÀ perheittÀin esiintyvissÀ liikehÀiriöissÀ. LisÀksi selvitettiin eksomisekvensoinnin kÀyttökelpoisuutta kliinisessÀ diagnostiikassa nÀiden potilasryhmien kohdalla. Tutkimukseen osallistui yhteensÀ 12 sisÀÀnottokriteerit tÀyttÀvÀÀ lasta, joiden sairauden syy oli jÀÀnyt tuntemattomaksi.
GABRG2-geenin mutaatiot aiheuttivat epileptisiÀ enkefalopatioita, joiden uutena ilmiasuna oli etenevÀ taudinkuva, johon liittyivÀt aivojen rappeutuminen, migroiva imevÀisiÀn paikallisalkuinen epilepsia sekÀ autismikirjon hÀiriö. Tutkimuksessa löydettiin uusia GABRG2-mutaatioita: p.P282T ja p.S306F.
NACC1-geenin mutaatio aiheutti epilepsian, kehitysvammaisuuden, molemminpuolisen kaihin ja autonomisen hermoston toiminnan hÀiriön. Hyperkineettinen liikehÀiriö oli uusi NACC1 p.R298W -mutaatioon liittyvÀ ilmiasu.
SAMD9L-geenin mutaatio aiheutti perheessÀ esiintyvÀn liikehÀiriön. Neurologinen ja hematologinen ilmiasu olivat hyvin vaihtelevia. Aivojen kuvantamislöydöksiin sisÀltyi pikkuaivojen rappeutumista ja valkoisen aivoaineen muutoksia aivokammioiden ympÀrillÀ. NÀiden tutkimustulosten julkaisemisen jÀlkeen SAMD9L-geenin mutaatioiden on todettu olevan yksi yleisimmistÀ perinnöllisistÀ luuytimen vajaatoiminnan ja myelodysplasian syistÀ.
Homotsygoottinen MTR-geenin mutaatio aiheutti varhain alkaneen epileptisen enkefalopatian, liikehÀiriön ja hematologisen hÀiriön. Kofaktori- ja vitamiini hoidot vÀhensivÀt epileptisiÀ kohtauksia, joihin tavanomainen lÀÀkitys ei tehonnut.
Geneettiset syyt ja ilmiasut ovat epileptisissÀ enkefalopatioissa ja liikehÀiriöissÀ hyvin vaihtelevia, ja osaan on olemassa spesifi hoito. Eksomisekvensointi on kÀyttökelpoinen diagnostiikan ja uusien geneettisten syiden etsimisen apuna. TÀssÀ tutkimuksessa eksomisekvensoinnin avulla kymmenestÀ potilaasta kahdelle (20 %) saatiin varmistettua geneettinen diagnoosi
Ei-epileptiset kohtausoireet imevÀiÀssÀ
TiivistelmÀ
Ei-epileptiset kohtausoireet ovat imevÀisiÀssÀ yleisempiÀ kuin epileptiset kohtaukset.
Useimmat kohtaukselliset liikehÀiriöt normaalisti kehittyvÀllÀ imevÀisellÀ ovat hyvÀennusteisia ja vÀistyvÀt itsestÀÀn lapsen kasvaessa.
Osassa ei-epileptisistÀ kohtauksista tarvitaan jatkotutkimuksia, mutta usein oireiden luonne selviÀÀ jo vanhempien kuvauksen perusteella, eikÀ lisÀselvittelyjÀ kotivideon lisÀksi tarvita.
On tÀrkeÀÀ tunnistaa yleisimmÀt ei-epileptiset kohtaukset kalliiden ja lasta rasittavien tutkimusten sekÀ turhien, mahdollisesti haittavaikutuksia aiheuttavien lÀÀkitysten vÀlttÀmiseksi.English summary
Paroxysmal non-epileptic events during infancy
Paroxysmal non-epileptic events are more common than epileptic seizures during infancy. In general, transient movement disorders of infancy have a good prognosis in normally developing children. In most cases, the typical clinical presentation and home videos are enough for diagnosis, but sometimes additional investigations are required. With the prompt diagnosis of paroxysmal non-epileptic event, unnecessary and exhausting investigations and potentially harmful medications can be avoided
Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders
Abstract
Purpose: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier â novel variants are discovered and new phenotypes described. Variants in the same gene â even the same variant â can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of epileptic encephalopathies in paediatric patients with complex phenotypes.
Methods: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. We searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features.
Results: We identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies.
Conclusion: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants
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HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein.
HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease. This article is protected by copyright. All rights reserved
Ataxia-pancytopenia syndrome with SAMD9L mutations
Abstract
Objective: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.
Methods: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.
Results: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.
Conclusions: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial
Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability
Peer reviewe
Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability
HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein
Abstract
HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease