Feasibility and acceptability of targeted salivary cytomegalovirus screening through universal newborn hearing screening.

AIM: This study aimed to determine the feasibility and parental acceptability of screening for congenital cytomegalovirus (cCMV) through saliva polymerase chain reaction in infants who did not pass their newborn hearing screening. Additionally, the utility (i.e. time to diagnosis and treatment) of this enhanced clinical pathway was evaluated. METHODS: The study was conducted through the Victorian Infant Hearing Screening Programme (VIHSP) across four maternity hospitals in Melbourne, Australia, during June 2019-March 2020. Parents were approached by VIHSP staff about obtaining a test for cytomegalovirus (CMV) at the time of their baby's second positive ('refer') result on the VIHSP screen. Participating parents collected a saliva swab for CMV polymerase chain reaction from their infants. Feasibility was determined by the proportion of 'referred' infants whose parents completed the salivary CMV screening test ≤21 days of life. Acceptability was measured through parent survey. RESULTS: Of 126 eligible families, 96 (76.0%) had salivary screening swabs taken ≤21 days of life. Most families (>92.0%) indicated that screening was acceptable, straightforward and thought testing their baby for cCMV was a good idea. One infant screened positive on day 30, was diagnosed with cCMV via confirmatory testing by day 31 and commenced valganciclovir on day 32. CONCLUSIONS: Obtaining a saliva sample to screen for cCMV in infants who do not pass their newborn hearing screen is feasible and appears acceptable to parents. This targeted cCMV screening method could be an option where mothers are rapidly discharged from hospital, especially in the context of the COVID-19 pandemic.

The use of listening devices to ameliorate auditory deficit in children with autism.

OBJECTIVES: To evaluate both monaural and binaural processing skills in a group of children with autism spectrum disorder (ASD) and to determine the degree to which personal frequency modulation (radio transmission) (FM) listening systems could ameliorate their listening difficulties. STUDY DESIGN: Auditory temporal processing (amplitude modulation detection), spatial listening (integration of binaural difference cues), and functional hearing (speech perception in background noise) were evaluated in 20 children with ASD. Ten of these subsequently underwent a 6-week device trial in which they wore the FM system for up to 7 hours per day. RESULTS: Auditory temporal processing and spatial listening ability were poorer in subjects with ASD than in matched controls (temporal: P = .014 [95% CI -6.4 to -0.8 dB], spatial: P = .003 [1.0 to 4.4 dB]), and performance on both of these basic processing measures was correlated with speech perception ability (temporal: r = -0.44, P = .022; spatial: r = -0.50, P = .015). The provision of FM listening systems resulted in improved discrimination of speech in noise (P < .001 [11.6% to 21.7%]). Furthermore, both participant and teacher questionnaire data revealed device-related benefits across a range of evaluation categories including Effect of Background Noise (P = .036 [-60.7% to -2.8%]) and Ease of Communication (P = .019 [-40.1% to -5.0%]). Eight of the 10 participants who undertook the 6-week device trial remained consistent FM users at study completion. CONCLUSIONS: Sustained use of FM listening devices can enhance speech perception in noise, aid social interaction, and improve educational outcomes in children with ASD.

Exome sequencing in infants with congenital hearing impairment: a population-based cohort study.

Congenital hearing impairment (HI) is the most common sensory impairment and can be isolated or part of a syndrome. Diagnosis through newborn hearing screening and management through early intervention, hearing aids and cochlear implantation is well established in the Australian setting; however understanding the genetic basis of congenital HI has been missing. This population-derived cohort comprised infants with moderate-profound bilateral HI born in the 2016-2017 calendar years, detected through newborn hearing screening. Participants were recruited through an integrated paediatric, otolaryngology and genetics HI clinic and offered whole exome sequencing (WES) on a HiSeq4000 or NextSeq500 (Illumina) platform with a targeted average sequencing depth of 100x and chromosome microarray on the Illumina Infinium core exome-24v1.2 platform. Of those approached, 68% (106/156) consented to participate. The rate of genetic diagnosis was 56% (59/106), significantly higher than standard of care (GJB2/6 sequencing only), 21% (22/106). There were clinical implications for the 106 participants: 36% required no further screening, 9% had tailored screening initiated, 2% were offered treatment and 4% had informed care for a complex neurodevelopmental syndrome. WES in this cohort demonstrates the range of diagnoses associated with congenital HI and confirms the genetic heterogeneity of congenital HI. The high diagnostic yield and clinical implications emphasises the need for genomic sequencing to become standard of care.

Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.

OBJECTIVE: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS: Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS: Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION: We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

Reducing Listening-Related Stress in School-Aged Children with Autism Spectrum Disorder.

High levels of stress and anxiety are common in children with Autism Spectrum Disorder (ASD). Within this study of school-aged children (20 male, 6 female) we hypothesised that functional hearing deficits (also pervasive in ASD) could be ameliorated by auditory interventions and that, as a consequence, stress levels would be reduced. The use of Ear-Level Remote Microphone devices and Classroom Amplification systems resulted in significantly improved listening, communication and social interaction and a reduction in physiologic stress levels (salivary cortisol) in both one-on-one and group listening situations.

A protocol for whole-exome sequencing in newborns with congenital deafness: a prospective population-based cohort.

INTRODUCTION: The aetiology of congenital hearing loss is heterogeneous, and in many infants a genetic cause is suspected. Parents face a diagnostic odyssey when searching for a cause of their infant's hearing loss. Through the Melbourne Genomics Health Alliance, a prospective cohort of infants will be offered whole-exome sequencing (WES) with targeted analysis in conjunction with chromosome microarray to determine the genetic causes of congenital hearing loss. Parents will also be offered the opportunity to receive additional results from their infant's WES. METHODS: Eligible infants will be identified through the Victorian Infant Hearing Screening Program and offered an appointment in a paediatrician-run clinic, a genetics assessment and enrolment in the Victorian Childhood Hearing Impairment Longitudinal Databank. If parents consent to WES, genes causing deafness will be analysed and they can choose to obtain additional findings. For the additional results component, a modified laboratory protocol has been designed for reporting of results in the absence of a relevant phenotype. Parents' experience of being offered WES will be evaluated using surveys. DISCUSSION: This project will provide descriptive analysis of the genetic aetiology of congenital hearing loss in this cohort and may provide data on genotype-phenotype correlations. Additionally, choices regarding additional findings will be analysed. Participants will represent a diverse cross section of the population, increasing the ability to generalise results beyond the study group. Evaluation surveys will allow analysis of preferences around counselling, usefulness of a decision aid and adequacy of information provision.

A retrospective case-control study of developmental and other outcomes in a cohort of Australian children conceived by intracytoplasmic sperm injection compared with a similar group in the United Kingdom.

OBJECTIVE: To investigate the possibility that children born after ICSI were at increased risk for neurodevelopmental delay. DESIGN: Retrospective case-control study. SETTING: IVF clinic. PATIENT(S): Fifty-eight singleton children born after ICSI and 38 normally conceived singleton children (controls), matched for relevant sociodemographic characteristics, from Australia and 208 case-patients and 221 controls from the United Kingdom. MAIN OUTCOME MEASURE(S): Antenatal and perinatal, and sociodemographic characteristics; physical health, including congenital abnormalities; and neurodevelopment by using the Griffiths scales of mental development. RESULT(S): Eighty-five percent of case-patients and 96% controls were assessed at a mean age of 13 months. Neurodevelopmental scores were similar in all children. Perinatal outcome was similar, apart from more caesarean sections in the case-patients. Rates of congenital anomalies were similar (5.6% among case-patients vs. 5.7% among controls). Children from fathers with oligozoospermia showed no extra problems. Children born after ICSI in the United Kingdom and Australia were similar. CONCLUSION(S): Children conceived after ICSI did not differ from their naturally conceived peers in physical health or development at ages up to 15 months.

Motor proficiency and emotional/behavioural disturbance in autism and Asperger's disorder: another piece of the neurological puzzle?

The relationship of motor proficiency with emotional/behavioural disturbance, autistic symptoms and communication disturbance was investigated in children diagnosed with autism and Asperger's disorder (AD). The Movement Assessment Battery for Children was used as a measure of motor impairment, and the Developmental Behavioural Checklist was used as a measure of emotional/behavioural disturbance in the following groups: AD (n = 22), high functioning autism (HFA) (n = 23), LFA (n = 8) and typically developing children (n = 20). The HFA group had more difficulty with motor items, such as ball skills and balance, than did the AD group. There were significant positive correlations between impairments in motor proficiency (in particular ball skills and balance) and emotional/behavioural disturbance, autistic symptoms and communication disturbance. These findings are consistent with the hypothesis that there are qualitative and quantitative differences in the motor profile between autism and AD. In addition, the association between motor proficiency impairment and emotional/behavioural disturbance in autism and AD emphasizes the importance for screening of co-occurring emotional/behavioural symptoms in individuals with motor difficulties. These findings have implications for the potential use of adjunct motor measures in the diagnosis and definition of autism spectrum disorders.