Autistic traits and speech perception in social and non-social noises.

Individuals with the autism spectrum disorder (ASD) experience difficulties in perceiving speech in background noises with temporal dips; they also lack social orienting. We tested two hypotheses: (1) the higher the autistic traits, the lower the performance in the speech-in-noise test, and (2) individuals with high autistic traits experience greater difficulty in perceiving speech, especially in the non-vocal noise, because of their attentional bias toward non-vocal sounds. Thirty-eight female Japanese university students participated in an experiment measuring their ability to perceive speech in the presence of noise. Participants were asked to detect Japanese words embedded in vocal and non-vocal background noises with temporal dips. We found a marginally significant effect of autistic traits on speech perception performance, suggesting a trend that favors the first hypothesis. However, caution is needed in this interpretation because the null hypothesis is not rejected. No significant interaction was found between the types of background noise and autistic traits, indicating that the second hypothesis was not supported. This might be because individuals with high autistic traits in the general population have a weaker attentional bias toward non-vocal sounds than those with ASD or to the explicit instruction given to attend to the target speech.

Internalizing problems and suffering due to sensory symptoms in children and adolescents with and without autism spectrum disorder.

Sensory symptoms are common in autism spectrum disorder (ASD). Previous studies have shown a positive correlation between sensory symptoms and internalizing problems; however, the role of the suffering due to sensory symptoms is not well understood. In the present study, we hypothesized that the relationship between sensory symptoms and internalizing problems in children is mediated by children's and surrounding people's suffering due to sensory symptoms. Parents of 113 students aged 6-15 years with and without ASD completed questionnaires about their children's autistic traits, sensory symptoms, suffering due to sensory symptoms, and internalizing problems. The results showed that autistic traits and sensory symptoms were distributed as a continuum throughout children with and without ASD. Therefore, we investigated the relationship among variables in children with and without ASD attending regular classes. Structural equation modeling indicated that those who scored higher on sensory symptoms demonstrated greater suffering due to sensory symptoms as predictors of internalizing problems. Our findings provide evidence for developing a support system that specifically reduces suffering due to sensory symptoms, especially for students in regular classes.

Mediating role of sensory differences in the relationship between autistic traits and internalizing problems.

BACKGROUND: Sensory differences are related to the autistic traits, and previous studies have shown a positive correlation between sensory differences and internalizing problems. In this study, we hypothesized that sensory differences and suffering due to sensory differences mediates the relationships between autistic traits and internalizing problems. METHODS: A total of 346 female Japanese university students completed questionnaires regarding their autistic traits, suffering due to sensory differences, and internalizing problems. Moreover, 114 participants completed a questionnaire related to sensory differences. RESULTS: Autistic traits were correlated with Low Registration and Sensation Avoiding. These sensory differences were also correlated with suffering due to sensory differences and internalizing problems. Moreover, path analysis indicated that the higher the suffering due to Low Registration and Sensation Avoiding was, the greater the internalizing problems in those who showed these sensory differences. CONCLUSIONS: Female university students with serious suffering due to sensory differences may need support in managing their suffering and internalizing problems. Further research will help suggest support that these people require, at school and elsewhere.

Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome.

INTRODUCTION: Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or -KTS]), and imbalance of the +KTS/-KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated. METHODS: We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/-KTS ratio using patients' samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype. RESULTS: The in vitro assay revealed that although all mutant alleles produced -KTS transcripts only, the wild-type allele produced both +KTS and -KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients' samples with all heterozygous variants produced similar ratios of +KTS to -KTS (1:3.2-1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period. CONCLUSION: Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS.

Genotype-Phenotype Correlation in WT1 Exon 8 to 9 Missense Variants.

INTRODUCTION: WT1 missense mutation in exon 8 or 9 causes infantile nephrotic syndrome with early progression to end-stage kidney disease (ESKD), Wilms tumor, and 46,XY female. However, some patients with missense mutations in exon 8 or 9 progress to ESKD in their teens or later. Therefore, we conducted a systematic review and functional analysis of WT1 transcriptional activity. METHODS: We conducted a systematic review of 174 cases with WT1 exon 8 or 9 missense variants from our cohort (n=13) and previous reports (n=161). Of these cases, mild and severe genotypes were selected for further in vitro functional analysis using luciferase assay. RESULTS: The median age of developing ESKD was 1.17 years. A comparative study was conducted among three WT1 genotype classes: mutations of the DNA-binding site (DBS group), mutations outside the DNA-binding site but at sites important for zinc finger structure formation by 2 cysteines and 2 histidines (C2H2 group), and mutations leading to other amino acid changes (Others group). The DBS group showed the severest phenotype and the C2H2 group was intermediate, whereas the Others group showed the mildest phenotype (developing ESKD at 0.90, 2.00, and 3.92 years, respectively, with significant differences). In vitro functional analysis showed dominant-negative effects for all variants; in addition, the DBS and C2H2 mutations were associated with significantly lower WT1 transcriptional activity than the other mutations. CONCLUSION: Not only the DNA-binding site but also C2H2 zinc finger structure sites are important for maintaining WT1 transcriptional activity, and their mutation causes severe clinical symptoms.

Detection of a Splice Site Variant in a Patient with Glomerulopathy and Fibronectin Deposits.

BACKGROUND/AIMS: Glomerulopathy with fibronectin deposits (GFND; OMIM: 601894) is a very rare inherited kidney disease caused by pathogenic variants in the FN1 gene. Only 9 exonic pathogenic variants in FN1, 9 at the heparin-binding site, and 1 at the integrin-binding site have been reported. No intronic variants in FN1 have been detected. METHODS: We found a pathogenic intronic variant in intron 36 (c.5888-2A>G) located at the heparin-binding site. To determine whether this mutation influences splicing processes, we conducted RT-PCR analysis and an in vitro splicing assay using minigene construction. RESULTS: RT-PCR using RNA extracted from leukocytes of the proband failed because of the low expression of FN1 mRNA in leukocytes. We conducted in vitro functional splicing analysis using minigenes and found that c.5888-2A>G caused a 12 bp deletion at exon 37 by the activation of a novel splicing acceptor site within exon 37. We were able to detect the same abnormal transcript in mRNA extracted from the patient's urinary sediment and confirmed the pathogenicity of c.5888-2A>G by both RT-PCR using the patient sample and an in vitro splicing assay. CONCLUSION: Intronic variants can cause GFND. Minigene analysis is useful for determining the pathogenicity of the intronic variants and could be used for all inherited kidney diseases.