Extended genetic diagnostics for children with profound sensorineural hearing loss by implementing massive parallel sequencing. Diagnostic outcome, family experience and clinical implementation.

OBJECTIVES: The aim of this study was to investigate genetic outcomes, analyze the family experience, and describe the process of implementing genetic sequencing for children with profound sensorineural hearing loss (SNHL) at a tertial audiological center in southern Sweden. DESIGN: This is a prospective pilot study including eleven children with profound bilateral SNHL who underwent cochlear implant surgery. Genetic diagnostic investigation was performed with whole exome sequencing (WES) complemented with XON-array to identify copy number variants, using a manually curated gene panel incorporating 179 genes associated with non-syndromic and syndromic SNHL. Mitochondrial DNA (mtDNA) from blood was examined separately. A patient reported experience measures (PREM) questionnaire was used to evaluate parental experience. We also describe here the process of implementing WES in an audiology department. RESULTS: Six female and five male children (mean 3.4 years, SD 3.5 years), with profound bilateral SNHL were included. Genetic variants of interest were found in six subjects (55%), where three (27%) could be classified as pathogenic or likely pathogenic. Among the six cases, one child was found to have a homozygous pathogenic variant in MYO7A and two children had homozygous likely pathogenic variants in SLC26A4 and PCDH15, respectively. One was carrying a compound heterozygote frameshift variant of uncertain significance (VUS) on one allele and in trans, a likely pathogenic deletion on the other allele in PCDH15. Two subjects had homozygous VUS in PCDH15 and ADGRV1, respectively. In five of the cases the variants were in genes associated with Usher syndrome. For one of the likely pathogenic variants, the finding was related to Pendred syndrome. No mtDNA variants related to SNHL were found. The PREM questionnaire revealed that the families had difficulty in fully understanding the results of the genetic analysis. However, the parents of all eleven (100%) subjects still recommended that other families with children with SNHL should undergo genetic testing. Specifically addressed referrals for prompt complementary clinical examination and more individualized care were possible, based on the genetic results. Close clinical collaboration between different specialists, including physicians of audiology, audiologists, clinical geneticists, ophthalmologists, pediatricians, otoneurologists, physiotherapists and hearing habilitation teams was initiated during the implementation of the new regime. For all professionals involved, a better knowledge of the diversity of the genetic background of hearing loss was achieved. CONCLUSIONS: Whole exome sequencing and XON-array using a panel of genes associated with SNHL had a high diagnostic yield, added value to the families, and provided guidance for further examinations and habilitation for the child. Great care should be taken to thoroughly inform parents about the genetic test result. Collaborations between departments were intensified and knowledge of hearing genomics was increased among the staff.

Past-tense inflection of non-verbs: a potential clinical marker of developmental language disorder in Swedish children.

AIM: In this paper, we explore the performance of past-tense inflection of non-verbs (NVI) in children with developmental language disorder (DLD) and in typically developing controls, to investigate its accuracy as a clinical marker for Swedish-speaking children with DLD. Further, we investigate the relationship between NVI, nonword-repetition, and family history. METHODS: The sample consists of 36 children with DLD (mean age 9;5 years) and 60 controls (mean age 9;2 years). RESULTS: The DLD group performed significantly lower than the controls on the NVI task, with a large effect size of the difference (d = 1.52). Analysis of the clinical accuracy of NVI resulted in 80.6% sensitivity and 76.6% specificity. NVI was significantly and moderately associated with nonword-repetition in the controls, but not in the DLD group. A positive family history, 80.6% in the DLD group and 6.9% in the controls, was associated with lower performance on NVI. When controlling for group (DLD and controls), a non-significant association between family history and performance on the NVI task was found. CONCLUSIONS: NVI is a potential clinical marker of DLD in Swedish school-aged children, but the current NVI task does not reach the level of being acceptable. Further development of the NVI task is warranted to improve its accuracy.

Weak correlations between cerebellar tests.

Eyeblink conditioning, finger tapping, and prism adaptation are three tasks that have been linked to the cerebellum. Previous research suggests that these tasks recruit distinct but partially overlapping parts of the cerebellum, as well as different extra-cerebellar networks. However, the relationships between the performances on these tasks remain unclear. Here we tested eyeblink conditioning, finger tapping, and prism adaptation in 42 children and 44 adults and estimated the degree of correlation between the performance measures. The results show that performance on all three tasks improves with age in typically developing school-aged children. However, the correlations between the performance measures of the different tasks were consistently weak and without any consistent directions. This reinforces the view that eyeblink conditioning, finger tapping, and prism adaptation rely on distinct mechanisms. Consequently, performance on these tasks cannot be used separately to assess a common cerebellar function or to make general conclusions about cerebellar dysfunction. However, together, these three behavioral tasks have the potential to contribute to a nuanced picture of human cerebellar functions during development.

A Longer Interstimulus Interval Yields Better Learning in Adults and Young Adolescents.

Eyeblink conditioning is one of the most popular experimental paradigms for studying the neural mechanisms underlying learning and memory. A key parameter in eyeblink conditioning is the interstimulus interval (ISI), the time between the onset of the conditional stimulus (CS) and the onset of the unconditional stimulus (US). Though previous studies have examined how the ISI affects learning there is no clear consensus concerning which ISI is most effective and different researchers use different ISIs. Importantly, the brain undergoes changes throughout life with significant cerebellar growth in adolescents, which could mean that different ISIs might be called for in children, adolescents and adults. Moreover, the fact that animals are often trained with a shorter ISI than humans make direct comparisons problematic. In this study, we compared eyeblink conditioning in young adolescents aged 10-15 and adults using one short ISI (300 ms) and one long ISI (500 ms). The results demonstrate that young adolescents and adults produce a higher percentage of CRs when they are trained with a 500 ms ISI compared to a 300 ms ISI. The results also show that learning is better in the adults, especially for the shorter ISI.

Performance in eyeblink conditioning is age and sex dependent.

A growing body of evidence suggests that the cerebellum is involved in both cognition and language. Abnormal cerebellar development may contribute to neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), autism, fetal alcohol syndrome, dyslexia, and specific language impairment. Performance in eyeblink conditioning, which depends on the cerebellum, can potentially be used to clarify the neural mechanisms underlying the cerebellar dysfunction in disorders like these. However, we must first understand how the performance develops in children who do not have a disorder. In this study we assessed the performance in eyeblink conditioning in 42 typically developing children between 6 and 11 years old as well as in 26 adults. Older children produced more conditioned eyeblink responses than younger children and adults produced more than children. In addition, females produced more conditioned eyeblink responses than males among both children and adults. These results highlight the importance of considering the influence of age and sex on the performance when studying eyeblink conditioning as a measure of cerebellar development.

The Intra-Cochlear Impedance-Matrix (IIM) test for the Nucleus® cochlear implant.

OBJECTIVE: To describe the principles and operation of a new telemetry-based function test for the Nucleus® cochlear implant, known as the CS19 Intra-Cochlear Impedance Matrix (IIM) and to present results from a multicentre clinical study to establish reproducibility (test-retest reliability) and normative ranges. METHOD: The IIM test measures bipolar impedances between all electrode pairs and employs a normalization procedure based on common ground impedances in order to identify abnormal current paths among electrodes. Six European clinics collected IIM data from a total of 192 devices. RESULTS: Reproducibility was high between initial and repeat measurements. The normative analysis demonstrated narrow ranges among devices after normalization of impedance data. The IIM is able to identify abnormal current paths that are not evident from standard impedance telemetry and may otherwise only be found utilising average electrode voltage measurements (AEV). CONCLUSIONS: The IIM test was found to be straightforward to perform clinically and demonstrated reproducible data with narrow ranges in normally-functioning devices. Because this test uses a very low stimulation level the IIM test is well suited for children or multiply handicapped CI users who cannot reliably report on their auditory percepts. The new algorithms show potential to improve implant integrity testing capabilities if implemented in future clinical software.