ADAR Expression and Single Nucleotide Variants in Multiple Sclerosis Patients Affect the Response to Interferon Beta Therapy.

Interferon (IFN)-ß is the first-line disease management choice in multiple sclerosis (MS) with profound effects; however, in up to 50% of patients, clinical response does not occur. Ascertaining the responding state, need a long-term clinical follow-up, and this may lead to delay in use of other effective medications. IFN-induced cascade and its regulation is considered to play a major role in MS. Adenosine deaminase, RNA-specific (ADAR) dysregulation is important to IFN signaling pathway as an activity suppressor. Hence, we investigated the expression of ADAR and its single nucleotide variants of rs2229857 association with response to IFN-ß in relapsing-remitting MS patients. mRNA levels and genotyping of rs2229857 in 167 MS patients were investigated via SYBR Green real-time (RT)-quantitative polymerase chain reaction and high-resolution melting RT PCR, respectively. The allele-A in rs2229857 and higher expression of ADAR were associated with poor response to IFN-ß. Two response groups were significantly different in terms of annualized relapse rate, first symptoms, first extended disability status scale (EDSS), current EDSS, and the MS severity score. According to this study's findings, assessment of transcript levels and also variants in ADAR may be useful in identifying patients' response to IFN-ß before starting treatment. Further investigations are needed to determine the potency of ADAR to be a predictive biomarker in drug responsiveness.

Developmental and epileptic encephalopathy 89: A novel bi-allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile.

OBJECTIVE: Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult central nervous system, plays an important role during embryonic neural network formation. GAD67 is the rate-limiting enzyme in GABA synthesis, and its deficiency leads to developmental and epileptic encephalopathy 89 (DEE 89). Patients who suffered from this syndrome generally manifested severe to profound neurodevelopmental delay, seizures, and often congenital anomalies such as the cleft palate or/and omphalocele. Up to now, only three papers on this syndrome have been published, and our knowledge about the disease's clinical course and pathophysiology is in its infancy. METHODS: We used whole-exome sequencing (WES) and multiple in-silico tools to detect a potential causative variant in a patient with severe neurodevelopmental delay and refractory epilepsy. Moreover, by molecular docking and molecular dynamics simulation, we investigate the effect of the candidate variant on the GAD67 function and structure. RESULTS: WES data analysis revealed a novel deleterious variant (NM_000817.3: c.850C>T; p.Leu284Phe) in the GAD1 gene, which encodes the GAD67 enzyme. Molecular docking and molecular dynamics simulation showed that this variant has deleterious effects on the structure and function of the GAD67. This study's patient, in addition to typical symptoms of the DEE89, showed microcephaly and clonus in the toe, which were novel clinical findings. SIGNIFICANCE: Our findings expand the mutational and clinical spectrum of DEE 89. Also, by gathering clinical symptoms and genetic findings of previously reported cases, moreover providing a comprehensive clinical picture of the disease, we found that there was no common drug therapy among patients whose epilepsy was controlled. Furthermore, the comparison of clinical symptoms between patients with missense and truncating mutations did not show any significant clinical difference, except that patients with missense mutations did not show cleft palates or omphaloceles.

A Novel Biallelic Variant in CDH23 Gene in a Family with Atypical USH1D Manifestation: A Literature Review and Investigation of Genotype-Phenotype Correlation.

INTRODUCTION: Usher syndrome (USH) is an autosomal recessive disorder that predominantly affects hearing, vision, and, in some cases, vestibular function. USH, according to the onset age, severity, and progression of symptoms, is categorized into four main types. In addition, there are a significant number of reports that patients' manifestations deviate from canonical phenotypic criteria of main types of USH, which are named atypical USH. CDH23 is the second most common USH gene in which its defects result in USH1D, non-syndromic autosomal recessive deafness-12 (DFNB12), and in a few cases, atypical USH1D. While some studies have suggested that missense and truncating damaging variants in the CDH23 gene cause DFNB12 and USH1D, respectively, no genotype-phenotype correlation for atypical USH1D has been established. METHODS: Using whole-exome sequencing, we studied an Iranian family with two affected siblings who manifested congenital bilateral hearing loss, late-onset nyctalopia, retinitis pigmentosa, and normal vestibular function, indicating that their clinical symptoms are consistent with USH2. RESULTS: Whole-exome data analysis revealed a novel bi-allelic nonsense variant (c.6562G>T; p.Glu2188Ter) in the CDH23 gene, which was confirmed by Sanger sequencing. Surprisingly, CDH23 is a member of the USH1 genes; therefore, our patients suffered from atypical USH1D. Also, by conducting a literature review, we provided a clinical and mutational profile of all reported patients with atypical manifestations or those who refuted the claimed genotype-phenotype correlation. CONCLUSION: By reporting a novel damaging variant, we expand the mutational spectrum of the CDH23 gene that leads to atypical USH1D. Also, reviewing the literature shows that, contrary to previous claims, different genotypes occur in the CDH23 gene allelic disorders, and there is no clear-cut genotype-phenotype correlation.

Griscelli syndrome type 1: a novel pathogenic variant, and review of literature.

Griscelli syndrome type 1 (GS1) is a rare inherited autosomal recessive disease caused by a deleterious variant in the MYO5A gene and characterized by general hypopigmentation, neurological symptoms, motor disability, hypotonia, and vision abnormality. Only nine pathogenic variants in the MYO5A gene have been confirmed in association with the GS1. All of the reported pathogenic variants are truncating. Herein, two siblings from a consanguineous Iranian family with abnormal pigmentation and neurological symptoms were referred for genetic counseling. Whole-exome sequencing (WES) revealed a novel homozygous truncating variant c.1633_1634delAA (p.Asn545Glnfs*10) in the MYO5A gene, which was completely co-segregated with the phenotype in all affected and unaffected family members. Computational analysis and protein modeling demonstrated the deleterious effects of this variant on the structure and function of the protein. The variant, according to ACMG guidelines, was classified as pathogenic. Besides the novelty of the identified variant, our patients manifested more severe clinical symptoms and presented distal hyperlaxity in all four limbs, which was a new finding. In conclusion, we expanded the mutational and phenotypic spectrum of the GS1. Moreover, by studying clinical manifestations in all molecularly confirmed reported cases, provided a comprehensive overview of clinical presentation, and attempted to find a genotype-phenotype correlation.

Interdependency of NINJ2 gene expression and polymorphism with susceptibility and response to interferon beta in patients with multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a multifactorial inflammatory and autoimmune condition that lead to chronic neurodegeneration and central nervous system (CNS) demyelination that mainly affects young adults. The incidence and prevalence rate of MS considerably vary in ethnicities and geographic regions and affecting women more than men. Interferon-ß (IFN-ß) is the first-line disease management for MS, while the majority of affected members does not respond to the IFN-ß. Numerous recent studies shown a significant relationship between genetic variations and responsiveness to the IFN-ß. Therefore, determining the genetic differences in the drug response could help determine precise treatment strategies. METHODS: The genotyping of the rs7298096 polymorphism (SNP) and NINJ2 gene expression were assessed in 99 responders and 106 non-responder patients with IFN-ß treated RRMS. RESULTS: The distribution of rs7298096 SNP was significantly different in the responders and non-responder patients and the NINJ2 gene expression considerably increased in the non-responder patients compare to the responders. The NINJ2 gene expression level in the AA genotype of the non-responder group was higher than to the other genotypes of both groups. CONCLUSION: Our results showed that the NINJ2 gene expression level and rs7298096 genotype possibly affect the response to the IFN-ß in patients with RRMS.

Expression and clinical significance of IL7R, NFATc2, and RNF213 in familial and sporadic multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disorder of the central nervous system characterized by myelin loss and axonal dysfunction. Increased production of inflammatory factors such as cytokines has been implicated in axon destruction. In the present study, we compared the expression level of IL7R, NFATc2, and RNF213 genes in the peripheral blood of 72 MS patients (37 familial MS, 35 sporadic MS) and 74 healthy controls (34 individuals with a family history of the disease, 40 healthy controls without a family history) via Real-time PCR. Our results showed that the expression level of IL7R was decreased in the sporadic patients in comparison with other groups. Additionally, there was an increased NFATc2 expression level in MS patients versus healthy controls. Increased expression of NFATc2 in sporadic and familial groups compared to the controls, and familial group versus FDR was also seen. Our results also represented an increased expression level of RNF213 in familial patients as compared to the control group. The similar RNF213 expression between sporadic and control group, as well as FDR and familial group was also seen. Diagnostic evaluation was performed by receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) calculation. The correlation of clinical parameters including onset age and Expanded Disability Status Scale (EDSS) with our gene expression levels were also assessed. Overall, decreased expression level of IL7R in the sporadic cases and increased expression level of NFATc2 may be associated with the pathogenesis of MS disease. Confirmation of the effects of differential expression of RNF213 gene requires further studies in the wider statistical populations.

Gene expression profiles of YAP1, TAZ, CRB3, and VDR in familial and sporadic multiple sclerosis among an Iranian population.

Alterations in the regulatory mechanisms that control the process of myelination in the nervous system, may lead to the impaired myelination in the Multiple sclerosis. The Hippo pathway is an important mediator of myelination in the nervous system and might contribute to the pathophysiology of MS. This study examined via qPCR the RNA expression of YAP1, TAZ, and CRB3 as the key effectors of the Hippo pathway and also, VDR in the peripheral blood of 35 sporadic, 37 familial MS patients; and also 34 healthy first-degree relatives of the familial MS patients (HFR) and 40 healthy individuals without a family history of the disease (control). The results showed the increased expression of VDR in the sporadic group, as compared to other groups. There was also an increased expression of TAZ in the familial and HFR groups, as compared to the control group. The familial and sporadic patients displayed a significantly lower level of expression of YAP1 in comparison to the HFR group. The increased expression level in the sporadic patients and control group, as compared to the HFR group, was seen in CRB3. We also assessed different clinical parameters and MRI characteristics of the patients. Overall, these findings suggest that Hippo pathway effectors and also VDR gene may play a potential role in the pathophysiology of the sporadic and familial forms of MS. Confirmation of different gene expression patterns in sporadic and familial MS groups may have obvious implications for the personalization of therapies in the disease.

Identification of a Missense Variant in the EIF2B3 Gene Causing Vanishing White Matter Disease with Antenatal-Onset but Mild Symptoms and Long-Term Survival.

Vanishing white matter disease (VWM) is a rare autosomal recessive leukodystrophy caused by a mutation in any of the five gene encoding subunits of the translation initiation factors eIF2B1 to eIF2B5. Whole-exome sequencing was performed on a 7-year-old boy with prenatal symptoms, including intrauterine-growth retardation, decreased movements, and oligohydramnios as well as mild intellectual disability, optic atrophy, macrocephaly, mild ataxia, and white matter lesions after birth. Analysis of WES data revealed a homozygous missense variant, c.C590T (p.Thr197Met) in the EIF2B3 gene (NM_0203650). The candidate variant was confirmed by Sanger sequencing and found to co-segregate with disease in family members. Pathogenicity analysis, 3D protein modeling, and stability assessment showed the deleterious effects of this nucleotide change. Previous studies suggest a direct relationship between the onset of symptoms and the progression rate and severity of the disease. All described cases of EIF2B deficiency with antenatal-onset led prenatal death; if they were born, they experienced clinical exacerbation, seizure, severe encephalopathy, and consequent infantile death (< 1 year). The patient of this study had never had seizure, which could be a potential explanation for the observed mild clinical picture, chronic state, and long-term survival until the age of seven. This study reported the first VWM due to EIF2B gene deficiency with antenatal-onset but mild symptoms and long-term survival. The result of this study showed that stressor factors, particularly seizure, could have a substantial role in poor prognosis and early neonatal death.

Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature.

In recent years, the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia, named spastic paraplegia type 57 (SPG57). Until now, four pathogenic homozygous variants of the TFG gene have been reported associated with SPG57. Two consanguineous Iranian families (1 and 2), the first one with two affected members and the second one with one, all with an early-onset progressive muscle weakness, spasticity, and several neurological symptoms were examined via the whole-exome sequencing. Two homozygous missense variants including c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) have been found in the related families. The candidate variants were confirmed by Sanger sequencing and found to co-segregate with the disease in families. The bioinformatics analysis showed the deleterious effects of these nucleotide changes and the variants were classified as pathogenic according to ACMG guidelines. A comparison of the clinical presentation of the patients harboring c.41A>G (p.Lys14Arg) with previously reported SPG57 revealed variability in the severity state and unreported clinical presentation, including, facial atrophy, nystagmus, hyperelastic skin, cryptorchidism, hirsutism, kyphoscoliosis, and pectus excavatum. The affected member of the second family carried a previously reported homozygous c.316C>T (p.Arg106Cys) variant and displayed a complex HSP including optic atrophy. Remarkable clinical differences were observed between the family 1 and 2 harboring the c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) variants, which could be attributed to the distinct affected domains (PB1 domains and coiled-coil domains), and therefore, SPG57 might have been representing phenotype vs. variant position correlation.

An interdependence between GAPVD1 gene polymorphism, expression level and response to interferon beta in patients with multiple sclerosis.

Interferon-ß (IFN-ß) is among the first drugs used for reducing the symptoms of multiple sclerosis (MS). Many studies show that the genetic predisposition of patients might modulate their response to IFN-ß treatment. In this study GAPVD1 gene expression and the genotyping of rs2291858 variant were analysed in 100 responder and 100 non-responder patients with MS treated using IFN-ß. Moreover, rs2291858 genotyping was performed for 200 patients with MS and 200 healthy controls. GAPVD1 expression was significantly increased in the responder patients than in non-responders and the distribution of rs2291858 polymorphism was significantly different between them. The GAPVD1 expression level in AA genotype of the responder group was higher than that in other genotypes of these two groups. The results show that the GAPVD1 expression level and rs2291858 genotype probably affect the response to IFN- ß in patients with MS.

Connection of miR-185 and miR-320a expression levels with response to interferon-beta in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by neurodegeneration in the CNS. Interferon-beta (IFN-ß) is an FDA-approved drug used as the first-line treatment for relapse-remitting multiple sclerosis (RRMS). The exact mechanism of IFN-ß during the treatment of RRMS still remains unknown. Recently, many studies have shifted towards the role of miRNAs in the treatment of MS patients. METHODS: Herein, the expression level of miR-185-5p and miR-320a has been evaluated in order to candidate them as novel biomarkers for monitoring the response to IFN-ß therapy. For this purpose, one-hundred whole blood samples from patients with RRMS were collected, consisting of 50 responders and 50 non-responders to IFN-ß therapy. To predict the possible molecular mechanisms of IFN-ß and highlight the role of these miRNAs, in silico analysis was applied to enrich the signaling pathways which may be involved based on the target genes of miR-185-5p and miR-320a. RESULTS: It is identified that the differentially expressed miR-185-5p was statistically significant between the two treated groups with IFN-ß. Furthermore, MAPK signaling pathway was suggested as the main non-canonical pathway involved in IFN-ß therapy. CONCLUSION: miR-185-5p could be considered as a novel biomarker for monitoring the response to IFN-ß therapy.

miR-504 expression level is increased in multiple sclerosis patients responder to interferon-beta.

Multiple sclerosis is immune-mediated disease of the central nervous system characterized by demyelination in axons. IFN-ß is first-line treatment of MS. Biomarkers are needed for early prediction of responders and non-responders to therapy in the first month of treatment to avoid further disabilities. In this study, we analyzed the expression level of miR-504 and miR-711 in 52 IFN-ß responder patients in comparison to 53 non-responders. In the next step, the in-silico analysis was used to enrich related signaling pathways. The expression level of miR-504 was significantly higher in patients who respond to IFN-ß therapy, compared with non-responders and we obtain related statistically significant KEGG molecular signaling pathways. Our findings suggest that miR-504 can be considered as a novel biomarker for response to IFN-b therapy.

A Novel Pathogenic Variant in NAGLU (N-Acetyl-Alpha-Glucosaminidase) gene Identified by Targeted Next-Generation Sequencing Followed by in Silico Analysis.

BACKGROUND: Mucopolysaccharidosis IIIB (MPS IIIB) (Sanfilippo Syndrome Type B; OMIM 252920) is an autosomal recessive metabolic disorder caused by mutations in the NAGLU gene which encode lysosomal enzyme N-acetyl-glucosaminidase, involved in degradation of complex polysaccharide, heparan sulfate. The disease is characterized by progressive cognitive decline and behavioral difficulties and motor function retardation. MATERIALS & METHODS: In this study, targeted exome sequencing was used in consanguineous parent (mother) of a deceased child with clinical diagnosis of mucopolysaccharidosis. Sanger sequencing was performed to confirm the candidate pathogenic variants in extended family members and segregation analysis. In silico pathogenicity assessment of detected variant using multiple computational predictive tools were performed. Computational docking using the Molegro Virtual Docker (MVD) 6.0.1 software applied to evaluate affinity binding of altered protein for its ligand, N-Acetyl-D-Glucosamine. Moreover, with I-TASSER software functional alterations between wild and mutant proteins evaluated. RESULTS: We identified a novel heterozygote deletion variant (c.1294-1304 del CTCTTCCCCAA, p.432LeufsX25) in the NAGLU gene. The variant was classified as pathogenic based on the American College of Medical Genetics and Genomics guideline. Computational docking with the Molegro Virtual Docker (MVD) 6.0.1 software confirmed different affinity binding of truncated protein for its ligand. Moreover, I-TASSER software revealed structural and functional alterations of mutant proteins. CONCLUSION: This study expands the spectrum of NAGLU pathogenic variants and confirms the utility of targeted NGS sequencing in genetic diagnosis and also the utility and power of additional family information.

Toward Noise Certification during Design: Airframe Noise Simulations for Full-Scale, Complete Aircraft.

An overview of a recent, NASA-sponsored effort to substantially advance simulation-based airframe noise prediction is presented. An accurate characterization of this component of aircraft noise requires a high-fidelity representation of the finer geometrical details associated with the landing gear and wing high-lift devices, such as slats and flaps, which constitute major noise sources. To achieve this ambitious goal, a systematic approach was followed to extend our current state-of-the-art computational tools to a full-scale, complete aircraft in landing configuration within a realistic flight environment. The work involved several phases: high-fidelity, large-scale, unsteady flow simulations; model-scale experiments in ground-based facilities; and farfield noise prediction for a full-scale, complete aircraft. The comprehensive aeroacoustic database generated during the course of the effort provided a wealth of relevant information for full validation and benchmarking of the advanced computational tools used in the present work. The database will also foster the development of simulation methodologies with improved predictive capabilities.

In silico analysis of SLC3A1 and SLC7A9 mutations in Iranian patients with Cystinuria.

Cystinuria is an autosomal recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from renal tubule and small intestine. Mutations in two genes: SLC3A1, encoding the heavy chain rbAT of the renal cystine transport system and SLC7A9, the gene of its light chain b0, + AT have a crucial role in the diseases. In our previous studies from Iranian populations with Cystinuria totally six and eleven novel mutations respectively identified in SLC3A1 and SLC7A9 genes. In this study, we conducted an in silico functional analysis to explore the possible association between these genetic mutations and Cystinuria. MutationTaster, PolyPhen-2, PANTHER, FATHMM. PhDSNP and MutPred was applied to predict the degree of pathogenicity for the missense mutations. Furthermore, Residue Interaction Network (RIN) and Intron variant analyses was performed using Cytoscape and Human Slicing Finder softwares. These genetic variants can provide a better understanding of genotype-phenotype relationships in patients with Cystinuria. In the future, the findings may also facilitate the development of new molecular diagnostic markers for the diseases.

Meta-Analysis of the Association between GABA Receptor Polymorphisms and Autism Spectrum Disorder (ASD).

Previous studies have reported the association of GABA receptor subunits B3, A5, and G3 single-nucleotide polymorphisms (SNPs) in chromosome 15q11-q13 with autism spectrum disorders (ASDs). However, the currently available results are inconsistent. This study aimed to investigate the association between ASD and the GABA receptor SNPs in chromosomal region 15q11-q13. The association was calculated by the overall odds ratio (OR) with a 95% confidence interval (CI). We used sensitivity analyses and the assessment of publication bias in our meta-analysis. Eight independent case-control studies involving 1408 cases and 2846 healthy controls were analyzed, namely, 8 studies for GABRB3 SNPs as well as 4 studies for GABRA5 and GABRG3 polymorphisms. The meta-analysis showed that GABRB3 polymorphisms in general are not significantly associated with autism [OR = 0.846 (95% CI): 0.595-1.201, I2 = 79.1%]. Further analysis indicated that no associations were found between GABRB3 SNPs and autism on rs2081648 [OR = 0.84 (95% CI) = 0.41-1.72, I2 = 89.2%] and rs1426217 [OR = 1.13 (95% CI) = 0.64-2.0, I2 = 83%]. An OR of 0.95 (95% CI) = 0.77-1.17 was reported (I2 = 0.0%) for GABRA5 SNPs and an OR of 0.96 (95% CI) = 0.24-3.81 was obtained from GABRG3 SNPs (I2 = 97.8%). This meta-analysis provides strong evidence that different SNPs of GABA receptor B3, A5, and G3 subunit genes located on chromosome 15q11-q13 are not associated with the development of autism spectrum diseases in different ethnic populations. However, in future research, large-scale and high-quality studies are necessary to confirm the results.

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

Variants in Human Prostacyclin Receptor Gene in Patients with Migraine Headache.

Objective: Prostaglandin I2 receptor plays a major physiologic role in the relaxation of arterial smooth muscle and vasodilation and possibly during migraine attacks. Therefore, in this study, the coding and noncoding exons and exon-intron boundaries of Prostaglandin I2 receptor gene were examined in patients with migraine headache and healthy controls and the potential effects of identified single nucleotide variations were evaluated using direct PCR-sequencing and in silico analysis. Method : In this study, the peripheral blood samples of 50 patients and 50 controls were examined to find any mutation in coding and noncoding exons and exon-intron boundaries of PTGIR gene. DNA was extracted and all the samples were amplified by polymerase chain reaction (PCR) and sequenced. Results: In this study, the patients had a mean age of 35.235 ± 10.99 years (range, 9-60 yrs.), and female to male ratio was 4:1 in this group. The controls had a mean age of 35.058 ± 11.116 years (range, 8-59 yrs.), and female to male ratio was 3.7:1.3 in this group. Two patients had mutations in exon 2. The first mutation was located in exon 2 (at amino acid position 251) of PTGIR gene at nucleotide position c.866A > T, a synonymous variant described previously in the database. The second mutation was located in exon 2 c.867G > A, which is a missense variant. Sequence analysis revealed high occurrence of previously reported intronic variants mostly in a homozygous statue. Conclusion: The data supported the hypothesis that mutations in PTGIR gene, particularly the mutation we described, should be considered even in cases of migraine. The presence of this mutation in patients with family history raises important issues regarding genetic counselling.

RIT2 Polymorphisms: Is There a Differential Association?

Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single-nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders.

Comparison of Computational and Experimental Microphone Array Results for an 18%-Scale Aircraft Model.

An 18%-scale, semispan model is used as a platform for examining the efficacy of microphone array processing using synthetic data from numerical simulations. Two hybrid RANS/LES codes coupled with Ffowcs Williams-Hawkings solvers are used to calculate 97 microphone signals at the locations of an array employed in the NASA LaRC 14×22 tunnel. Conventional, DAMAS, and CLEAN-SC array processing is applied in an identical fashion to the experimental and computational results for three different configurations involving deploying and retracting the main landing gear and a part-span flap. Despite the short time records of the numerical signals, the beamform maps are able to isolate the noise sources, and the appearance of the DAMAS synthetic array maps is generally better than those from the experimental data. The experimental CLEAN-SC maps are similar in quality to those from the simulations indicating that CLEAN-SC may have less sensitivity to background noise. The spectrum obtained from DAMAS processing of synthetic array data is nearly identical to the spectrum of the center microphone of the array, indicating that for this problem array processing of synthetic data does not improve spectral comparisons with experiment. However, the beamform maps do provide an additional means of comparison that can reveal differences that cannot be ascertained from spectra alone.