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1.
Hum Mol Genet ; 31(3): 440-454, 2022 02 03.
Article in English | MEDLINE | ID: mdl-34505148

ABSTRACT

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.


Subject(s)
F-Box Proteins , Intellectual Disability , Neurodevelopmental Disorders , F-Box Proteins/genetics , HEK293 Cells , HeLa Cells , Humans , Intellectual Disability/genetics , Mutation, Missense/genetics , Neurodevelopmental Disorders/genetics , Protein-Arginine N-Methyltransferases/genetics
2.
Neuropediatrics ; 55(2): 140-145, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37846133

ABSTRACT

Mitchell syndrome is a very rare genetic disorder due to a specific de novo gain-of-function variant in acyl-CoA oxidase 1 (ACOX1). So far, only five patients with this disease have been described worldwide. We present here two additional unrelated German patients found to carry the same heterozygous ACOX1 N237S variant through exome sequencing (ES). Both patients showed neurodegenerative clinical features starting from ∼4 to 5 years of age including progressive hearing loss, ataxia, ichthyosis, as well as progressive visual impairment leading to amaurosis, and died at the ages of 16 and 8 years, respectively. The first patient was clinically suspected to have anti-myelin oligodendrocyte glycoprotein-antibody-associated myelitis, but the disease course overall deteriorated despite extensive immunomodulatory therapy. The second patient was originally suspected to have a mitochondrial disorder due to intermittent elevated blood lactate. Since Mitchell syndrome has only been identified in 2020, the diagnosis in this second patient was only established through re-evaluation of ES data years after the original analysis. Comparison of all seven reported patients suggests that Mitchell syndrome often (but not always) clinically mimics autoimmune-inflammatory disease. Therefore, in patients with autoimmune central nervous system disease who do not respond adequately to standard therapies, re-evaluation of this diagnosis is needed and genetic analyses such as trio ES should be considered.


Subject(s)
Autoimmune Diseases , Gain of Function Mutation , Child , Humans , Myelin-Oligodendrocyte Glycoprotein , Vision Disorders
3.
Genet Med ; 25(4): 100003, 2023 04.
Article in English | MEDLINE | ID: mdl-36549593

ABSTRACT

PURPOSE: Transformer2 proteins (Tra2α and Tra2ß) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder. METHODS: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2ß-1 and Tra2ß-3 isoforms from patient-derived cells were performed. Tra2ß1-GFP, Tra2ß3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells. RESULTS: All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2ß-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2ß-1 isoform, whereas they increased the expression of the Tra2ß-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2ß-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2ß-1. CONCLUSION: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2ß protein.


Subject(s)
Autism Spectrum Disorder , Intellectual Disability , Neurodevelopmental Disorders , Humans , Alternative Splicing , RNA-Binding Proteins/genetics , HEK293 Cells , Protein Isoforms/genetics , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Serine-Arginine Splicing Factors/genetics , Serine-Arginine Splicing Factors/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism
4.
Int J Mol Sci ; 24(7)2023 Apr 06.
Article in English | MEDLINE | ID: mdl-37047781

ABSTRACT

BICD2 variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in BICD2 were implicated in myopathies. Here, we present one patient with a known and six patients with novel BICD2 missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy. Clinical and MRI-features revealed a typical pattern of distal paresis of the lower extremities as characteristic features of a BICD2-associated disorder. Histological evaluation showed myopathic features of varying severity including fiber size variation, lipofibromatosis, and fiber splittings. Proteomic analysis with subsequent fluorescence analysis revealed an altered abundance and localization of thrombospondin-4 and biglycan. Our combined clinical, histopathological, and proteomic approaches provide new insights into the pathophysiology of BICD2-associated disorders, confirming a primary muscle cell vulnerability. In this context, biglycan and thrombospondin-4 have been identified, may serve as tissue pathogenicity markers, and might be linked to perturbed protein secretion based on an impaired vesicular transportation.


Subject(s)
Microtubule-Associated Proteins , Muscular Atrophy, Spinal , Humans , Biglycan/metabolism , Microtubule-Associated Proteins/metabolism , Proteomics , Muscular Atrophy, Spinal/genetics , Mutation , Muscle, Skeletal/metabolism
5.
Int J Mol Sci ; 24(19)2023 Sep 28.
Article in English | MEDLINE | ID: mdl-37834164

ABSTRACT

Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding DMD gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (FKTN) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the DMD gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing.


Subject(s)
Muscular Dystrophy, Duchenne , Humans , Male , Chromosome Inversion , Chromosome Mapping , Dystrophin/genetics , Exome Sequencing , Muscular Dystrophy, Duchenne/diagnosis , Muscular Dystrophy, Duchenne/genetics , Mutation
6.
Genet Med ; 24(6): 1261-1273, 2022 06.
Article in English | MEDLINE | ID: mdl-35341651

ABSTRACT

PURPOSE: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. METHODS: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. RESULTS: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. CONCLUSION: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.


Subject(s)
DNA Methylation , Hypogonadism , Klinefelter Syndrome , Neurodevelopmental Disorders , SOXC Transcription Factors , DNA Methylation/genetics , Humans , Hypogonadism/genetics , Klinefelter Syndrome/genetics , Neurodevelopmental Disorders/genetics , Phenotype , SOXC Transcription Factors/genetics , Exome Sequencing
7.
Int J Mol Sci ; 23(24)2022 Dec 09.
Article in English | MEDLINE | ID: mdl-36555281

ABSTRACT

Deletions in the CCM1, CCM2, and CCM3 genes are a common cause of familial cerebral cavernous malformations (CCMs). In current molecular genetic laboratories, targeted next-generation sequencing or multiplex ligation-dependent probe amplification are mostly used to identify copy number variants (CNVs). However, both techniques are limited in their ability to specify the breakpoints of CNVs and identify complex structural variants (SVs). To overcome these constraints, we established a targeted Cas9-mediated nanopore sequencing approach for CNV detection with single nucleotide resolution. Using a MinION device, we achieved complete coverage for the CCM genes and determined the exact size of CNVs in positive controls. Long-read sequencing for a CCM1 and CCM2 CNV revealed that the adjacent ANKIB1 and NACAD genes were also partially or completely deleted. In addition, an interchromosomal insertion and an inversion in CCM2 were reliably re-identified by long-read sequencing. The refinement of CNV breakpoints by long-read sequencing enabled fast and inexpensive PCR-based variant confirmation, which is highly desirable to reduce costs in subsequent family analyses. In conclusion, Cas9-mediated nanopore sequencing is a cost-effective and flexible tool for molecular genetic diagnostics which can be easily adapted to various target regions.


Subject(s)
Carrier Proteins , DNA Copy Number Variations , Nanopore Sequencing , Humans , Carrier Proteins/genetics , CRISPR-Cas Systems , Multiplex Polymerase Chain Reaction
8.
Muscle Nerve ; 59(4): 484-486, 2019 04.
Article in English | MEDLINE | ID: mdl-30536747

ABSTRACT

INTRODUCTION: Mutations in the BICD2 gene are causative for an autosomal dominant form of spinal muscular atrophy (SMALED2). Further, BICD2 mutations have been implicated in hereditary spastic paraplegia (HSP), but only very few such patients have been described. In this report we aimed to investigate the frequency of BICD2 mutations in patients with HSP and hereditary motor and sensory neuropathy (HMSN) who were negative for the most common known genetic causes. METHODS: The cohorts comprised 171 HSP and 189 HMSN patients. Mutational analysis was performed with high-resolution melting analysis followed by Sanger sequencing. RESULTS: In both cohorts, we found no known or likely pathogenic mutations in the BICD2 gene. DISCUSSION: BICD2 mutations appear rather unlikely to cause a phenotype of HMSN and are a very rare cause of the HSP phenotype. Muscle Nerve 59:484-486, 2019.


Subject(s)
DNA Mutational Analysis , Hereditary Sensory and Motor Neuropathy/genetics , Microtubule-Associated Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Adult , Cohort Studies , Female , Genetic Linkage , Humans , Male , Mutation, Missense/genetics
9.
Neurogenetics ; 19(1): 55-59, 2018 01.
Article in English | MEDLINE | ID: mdl-29197946

ABSTRACT

Familial cerebral cavernous malformations (CCMs) predispose to seizures and hemorrhagic stroke. Molecular genetic analyses of CCM1, CCM2, and CCM3 result in a mutation detection rate of up to 98%. However, only whole genome sequencing (WGS) in combination with the Manta algorithm for analyses of structural variants revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial CCMs. Its breakpoints were fine-mapped, and quantitative analysis on RNA confirmed reduced CCM2 expression. Our data expand the spectrum of CCM mutations and indicate that the existence of a fourth CCM disease gene is rather unlikely.


Subject(s)
Carrier Proteins/genetics , Chromosome Inversion , Hemangioma, Cavernous, Central Nervous System/genetics , Brain/diagnostic imaging , Brain/pathology , Child , Genome-Wide Association Study , Hemangioma, Cavernous, Central Nervous System/diagnostic imaging , Hemangioma, Cavernous, Central Nervous System/pathology , Humans , Male , Pedigree , Whole Genome Sequencing
10.
BMC Neurol ; 18(1): 3, 2018 Jan 09.
Article in English | MEDLINE | ID: mdl-29316893

ABSTRACT

BACKGROUND: Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand. METHODS: We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the C9orf72 gene. RESULTS: Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in C9orf72. The analysis of the fragile X mental retardation 1 gene (FMR1) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats). CONCLUSIONS: Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller FMR1 gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for C9orf72 expansion in ataxia patients.


Subject(s)
Ataxia/genetics , C9orf72 Protein/genetics , DNA Repeat Expansion/genetics , Fragile X Syndrome/genetics , Nerve Tissue Proteins/genetics , Spinocerebellar Ataxias , Tremor/genetics , Adult , Cohort Studies , Female , Humans , Male , Middle Aged , Spinocerebellar Ataxias/epidemiology , Spinocerebellar Ataxias/genetics , Young Adult
12.
Hum Mol Genet ; 24(19): 5644-54, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-26188005

ABSTRACT

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.


Subject(s)
Adenosine Triphosphate/metabolism , Amino Acid Substitution , Multiple Sclerosis/genetics , Receptors, Purinergic P2X7/genetics , Receptors, Purinergic P2X7/metabolism , Arginine/metabolism , Australasia , Binding Sites , Genetic Association Studies , Genetic Predisposition to Disease , Glutamine/metabolism , Humans , Models, Molecular , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Receptors, Purinergic P2X7/chemistry , White People/genetics
13.
J Med Genet ; 53(8): 523-32, 2016 08.
Article in English | MEDLINE | ID: mdl-27075013

ABSTRACT

BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.


Subject(s)
Intellectual Disability/genetics , Mental Disorders/genetics , Proteins/genetics , Adult , Child , Child, Preschool , Cytoskeletal Proteins , Exons/genetics , Female , Genetic Association Studies/methods , Haploinsufficiency/genetics , Humans , Infant , Male , Microcephaly/genetics , Middle Aged , Mutation/genetics , Phenotype , Sequence Deletion/genetics , Syndrome , Transcription Factors , Young Adult
14.
J Genet Couns ; 26(5): 1029-1040, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28361381

ABSTRACT

We present a prospective study of counselees seeking predictive testing for Huntington's disease at the Huntington Center North Rhine-Westphalia (Bochum, Germany) between 2010 and 2012. The aim was to observe the decision-making process of at-risk individuals and explore their experiences following the decision as well as the impacts of positive and negative mutation results. Data were collected using two standardized questionnaires as well as via a semi-standardized telephone interview one year after the initial counseling session. Seventy-two  individuals participated in at least one of the three phases of the survey, including 31 individuals in the telephone interview. Sociodemographic data were in accordance with previous reports. The process of predictive testing was generally perceived in a positive manner, with almost all interviewees reporting a balanced emotional state one year after initial counseling, regardless of the decision for or against the test. The most important reasons named in favor of or against testing were assembled as well as different aspects regarding the satisfaction with the reached decision. In line with and expanding previous observations on gender-related differences in decision-making, our results suggest that gender-related aspects should be more strongly taken into account in genetic counseling during the predictive testing and counseling processes.


Subject(s)
DNA Mutational Analysis , Genetic Counseling/organization & administration , Genetic Testing/methods , Huntington Disease/genetics , Adult , Decision Making , Female , Humans , Male , Prospective Studies , Surveys and Questionnaires
15.
Neurogenetics ; 17(2): 131-5, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26865406

ABSTRACT

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by genome wide association studies and independent replication studies. A weighted genetic risk score (wGRS) was recently established using the identified MS risk loci in order to predict MS outcome including clinical and paraclinical features. Here, we present the results on a family with several affected siblings including a monozygotic triplet. The individuals were genotyped for 57 non-MHC risk loci as well as the HLA DRB1*1501 tagging SNP rs3135388 with subsequent calculation of the wGRS. Additionally, SNP array based analyses for aberrant chromosomal regions were performed for all individuals.


Subject(s)
Multiple Sclerosis/genetics , Child , Female , Genetic Loci , HLA-DRB1 Chains/genetics , Humans , Male , Pedigree , Polymorphism, Single Nucleotide , Risk Factors , Triplets , Young Adult
16.
Mol Cell Probes ; 30(6): 374-385, 2016 12.
Article in English | MEDLINE | ID: mdl-27725295

ABSTRACT

Atopic dermatitis (AD) is a common and complex skin disease associated with both genetic and environmental factors. Loss-of-function mutations in the filaggrin gene, encoding a structural protein with an important role in epidermal barrier function, constitutes a well recognised susceptibility locus for AD. Further, genome-wide association studies (GWAS), including large meta-analyses, have discovered 38 additional susceptibility loci with genome-wide significance. However, the reported variations only explain a fraction of the overall heritability of AD. Here, we summarize the current knowledge of the role of filaggrin and the epidermal differentiation complex as well as the results of GWAS, with an emphasis on novel findings and observations made in the past two years. Additionally, we present first results of exome sequencing for AD and discuss novel therapeutic strategies.


Subject(s)
Dermatitis, Atopic/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Mutation , Epidermis/metabolism , Epidermis/pathology , Exome/genetics , Filaggrin Proteins , Humans , Intermediate Filament Proteins/genetics , Sequence Analysis, DNA/methods
17.
Mol Cell Probes ; 30(1): 53-5, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26714052

ABSTRACT

The hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative diseases. Here, we evaluated the spectrum and frequency of mutations in the CYP7B1, PNPLA6 and C19orf12 genes (causative for the subtypes SPG5A, SPG39 and SPG43, respectively) in a cohort of 63 unrelated HSP patients with suspected autosomal recessive inheritance. Two novel homozygous mutations (one frameshift and one missense mutation) were detected in CYP7B1 (SPG5A), while no disease-causing mutation was identified for SPG39 or SPG43.


Subject(s)
Mitochondrial Proteins/genetics , Mutation , Phospholipases/genetics , Spastic Paraplegia, Hereditary/genetics , Steroid Hydroxylases/genetics , Adolescent , Adult , Base Sequence , Cohort Studies , Cytochrome P450 Family 7 , DNA Mutational Analysis/methods , Family Health , Female , Frameshift Mutation , Homozygote , Humans , Male , Mutation, Missense , Pedigree
18.
Mol Cell Probes ; 30(1): 44-9, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26790960

ABSTRACT

Mutations in the WDR45 gene have been identified as causative for the only X-linked type of neurodegeneration with brain iron accumulation (NBIA), clinically characterized by global developmental delay in childhood, followed by a secondary neurological decline with parkinsonism and/or dementia in adolescence or early adulthood. Recent reports suggest that WDR45 mutations are associated with a broader phenotypic spectrum. We identified a novel splice site mutation (c.440-2 A > G) in a 5-year-old Argentinian patient with Rett-like syndrome, exhibiting developmental delay, microcephaly, seizures and stereotypic hand movements, and discuss this finding, together with a review of the literature. Additional patients with a clinical diagnosis of Rett (-like) syndrome were also found to carry WDR45 mutations before (or without) clinical decline or signs of iron accumulation by magnetic resonance imaging (MRI). This information indicates that WDR45 mutations should be added to the growing list of genetic alterations linked to Rett-like syndrome. Further, clinical symptoms associated with WDR45 mutations ranged from early-onset epileptic encephalopathy in a male patient with a deletion of WDR45 to only mild cognitive delay in a female patient, suggesting that analysis of this gene should be considered more often in patients with developmental delay, regardless of severity. The increasing use of next generation sequencing technologies as well as longitudinal follow-up of patients with an early diagnosis will help to gain additional insight into the phenotypic spectrum associated with WDR45 mutations.


Subject(s)
Abnormalities, Multiple/genetics , Carrier Proteins/genetics , Developmental Disabilities , Mutation , Rett Syndrome , Abnormalities, Multiple/pathology , Base Sequence , Child, Preschool , DNA Mutational Analysis , Female , Humans , Male , Pedigree , RNA Splice Sites/genetics , Sequence Homology, Nucleic Acid
19.
J Med Genet ; 52(12): 848-55, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26475045

ABSTRACT

OBJECTIVE: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. METHODS: The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. RESULTS: Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10(-12)), CD28 (rs6435203, p=1.35×10(-9)), LPP (rs4686953, p=3.35×10(-8)), ETS1 (rs3809006, p=7.74×10(-9)), DLEU1 (rs806349, p=8.14×10(-12)), LPIN3 (rs6072343, p=7.16×10(-12)) and IFNGR2 (rs9808753, p=4.40×10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. CONCLUSIONS: This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.


Subject(s)
Multiple Sclerosis/genetics , Case-Control Studies , Gene Frequency , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , Risk Factors
20.
Mol Cell Probes ; 29(5): 319-22, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26327357

ABSTRACT

Mutations in the DARS2 gene are known to cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), a rare autosomal recessive neurological disorder. It was originally described as juvenile-onset slowly progressive ataxia and spasticity, but recent reports suggest a broader clinical spectrum. Most patients were found to carry compound heterozygous DARS2 mutations, and only very few patients with homozygous mutations have been described so far. We present here an 8-month-old boy carrying a homozygous missense mutation in DARS2 who clinically showed severe neurological deterioration after a respiratory tract infection, followed by an almost complete remission of symptoms. This report further extends the knowledge about the clinical and molecular genetic spectrum of LBSL.


Subject(s)
Aspartate-tRNA Ligase/genetics , Leukoencephalopathies/genetics , Mutation, Missense , Age of Onset , Genetic Predisposition to Disease , Homozygote , Humans , Infant , Leukoencephalopathies/diagnosis , Male , Pedigree , Sequence Analysis, DNA
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