A Genetic Basis for Mechanosensory Traits in Humans

Hearing and touch are genetically related, and people with excellent hearing are more likely to have a fine sense of touch and vice versa

Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome

Usher syndrome is an autosomal recessive disorder characterized both by deafness and blindness. For the three clinical subtypes of Usher syndrome causal mutations in altogether 12 genes and a modifier gene have been identified. Due to the genetic heterogeneity of Usher syndrome, the molecular analysis is predestined for a comprehensive and parallelized analysis of all known genes by next-generation sequencing (NGS) approaches. We describe here the targeted enrichment and deep sequencing for exons of Usher genes and compare the costs and workload of this approach compared to Sanger sequencing. We also present a bioinformatics analysis pipeline that allows us to detect single-nucleotide variants, short insertions and deletions, as well as copy number variations of one or more exons on the same sequence data. Additionally, we present a flexible in silico gene panel for the analysis of sequence variants, in which newly identified genes can easily be included. We applied this approach to a cohort of 44 Usher patients and detected biallelic pathogenic mutations in 35 individuals and monoallelic mutations in eight individuals of our cohort. Thirty-nine of the sequence variants, including two heterozygous deletions comprising several exons of USH2A, have not been reported so far. Our NGS-based approach allowed us to assess single-nucleotide variants, small indels, and whole exon deletions in a single test. The described diagnostic approach is fast and cost-effective with a high molecular diagnostic yield

Cross-correlations between the investigated sensory traits.

<p>Three different types of intramodal and intermodal correlations were distinguished (A). Three mechanosensory and one non-mechanosensory intermodal correlation were detected (B). ^ns, not significant; * <i>p</i><0.05; ** <i>p</i><0.01; *** <i>p</i><0.001. False discovery rates for <i>p</i> value cutoff at 0.05 for (1) intramodal correlations: 0.004, (2) mechanosensory intermodal correlations: 0.14, and (3) non-mechanosensory intermodal correlations: 0.83. Values were corrected for age before analysis.</p

Cross-twin correlations and heritability estimates of baroreflex traits.

<p>For both baroreflex traits—baroreflex sequence slope (A) and baroreflex sequence frequency (B)—the cross-twin correlations were higher in MZ than in DZ twins. Significant heritability estimates could be calculated. <i>r</i>, intra-class correlation; <i>h²</i>, heritability estimate; 95% confidence interval in brackets; AE, preferred model used to estimate heritability.</p

Cross-twin correlations and heritability estimates of hearing traits.

<p>For all three hearing traits—pure tone thresholds (A), otoacoustic emission reproducibility (B), and otoacoustic emission strength (C)—cross-twin correlations were higher in MZ than in DZ twins, and very high heritability values could be estimated. <i>r</i>, intra-class correlation; <i>h²</i>, heritability estimate; 95% confidence interval in brackets; AE, preferred model used to estimate heritability.</p

Cross-twin correlations and heritability estimates of touch sensitivity traits.

<p>For both vibration detection threshold (A) and tactile acuity (B) cross-twin correlations were higher in monozygotic (MZ) than in dizygotic (DZ) twins and significant heritability values could be estimated. <i>r</i>, intra-class correlation; <i>h²</i>, heritability estimate; 95% confidence interval in brackets; AE, preferred model used to estimate heritability.</p

Touch sensitivity in a cohort of Braille reading blind people.

<p>The vibration detection threshold was not different in comparison to a control cohort, but the tactile acuity was significantly higher in the blind cohort. *** <i>p</i><0.001; <i>t</i> test.</p

Touch sensitivity in different cohorts of people suffering from the Usher syndrome.

<p>The mean tactile acuity and vibration detection thresholds were elevated in the group of people carrying pathogenic mutations in the gene USH2A (A, B) but not in a cohort of Usher syndrome type II patients with unknown genotype where tactile acuity thresholds were lower than in the control cohort (D), and vibration detection thresholds were not significantly different (C). ^ns, not significant; * <i>p</i><0.05 Student's <i>t</i> test.</p

Summary of psychophysical and physiological tests carried out in different cohorts.

<p>Summary of psychophysical and physiological tests carried out in different cohorts.</p