David J Amor

• MBBS FRACP PhD
• Chair at Murdoch Children's Research Institute

Background: Congenital anomalies are a leading cause of perinatal mortality, with many having a genetic basis. Exome sequencing (ES) has transformed the diagnostic approach in the prenatal and post-mortem work-up of fetal congenital anomalies. Despite its benefits, population-based implementation programs that address equity and clinical consistenc...

Aim To examine the adaptive behaviour profiles of children with monogenic neurodevelopmental disorders (NDDs) to determine whether syndrome‐specific or transdiagnostic approaches provide a better understanding of the adaptive behavioural phenotypes of these NDDs. Method This cross‐sectional study included parents and caregivers of 243 (48% female)...

Objective Wearable technology has potential benefits for clinical measurement with children who have neurodevelopmental disorders (NDDs). However, this cohort may experience sensory processing disorder, behavioral dysregulation, and cognitive challenges. For effective and considerate implementation, the experiences and views of parents of children...

Purpose The TAOK proteins are a group of serine/threonine-protein kinases involved in signalling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia and feeding difficulties. TAOK2 variants have been reported to be...

Rare and typically severe motor speech disorders such as childhood apraxia of speech (CAS) and dysarthria affect about 1 in 1000 children. The genetic basis of these speech disorders is well-documented, with approximately 30% of children who undergo genomic testing receiving an explanatory genetic diagnosis. As more children with speech disorders a...

This study describes a protocol to assess a novel workflow called Epi-Genomic Newborn Screening (EpiGNs) on 100,000 infants from the state of Victoria, Australia. The workflow uses a first-tier screening approach called methylation-specific quantitative melt analysis (MS-QMA), followed by second and third tier testing including targeted methylation...

Background There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-...

Objectives Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in PURA cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual di...

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of...

The application of genomics has greatly increased the diagnosis of specific monogenic causes of intellectual disability and improved our understanding of the neuronal processes that result in cognitive impairment. Meanwhile, families are building rare disease communities and seeking disease‐specific treatments to change the trajectory of health and...

Observational studies have a critical role in disability research, providing the opportunity to address a range of research questions. Over the past decades, there have been substantial shifts and developments in statistical methods for observational studies, most notably for causal inference. In this review, we provide an overview of modern design...

Background There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-...

Introduction Newborn bloodspot screening (NBS) is a highly successful public health programme that uses biochemical and other assays to screen for severe but treatable childhood-onset conditions. Introducing genomic sequencing into NBS programmes increases the range of detectable conditions but raises practical and ethical issues. Evidence from pro...

Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69–24.34 years, with...

The disconnected (disco)‐interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase‐associated protein 1 (DMAP1) binding domain, Acyl‐CoA synthetase domain and AMP‐binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regenerati...

Severe speech disorders lead to poor literacy, reduced academic attainment and negative psychosocial outcomes. As early as the 1950s, the familial nature of speech disorders was recognized, implying a genetic basis; but the molecular genetic basis remained unknown. In 2001, investigation of a large three generational family with severe speech disor...

With increasing gene discoveries for severe speech disorders, genomic testing can alter the diagnostic and clinical paradigms, enabling better life outcomes for children and their families. However, evidence on the value of the outcomes generated is lacking, impeding optimal translation into health care. This study aims to estimate the value and up...

We sought to summarise recent research on prognostication in genetic neurodevelopmental conditions, focusing on parent preferences for prognostic conversations. We further aimed to explore recommendations about communicating children’s prognoses with parents at the time of diagnosis and beyond. Our review revealed growing research on prognostic con...

Objectives Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. Method 103...

Aim To investigate parents' preferences and motivations for receiving and discussing prognostic genetic test results. Method We used a cross‐sectional, interpretive description qualitative study design. We collected data through semi‐structured interviews with Australian parents, which we analysed using reflexive thematic analysis. Results Parent...

Purpose To our knowledge, there are no data examining the agreement between self-reported and clinician-rated stuttering severity. In the era of big data, self-reported ratings have great potential utility for large-scale data collection, where cost and time preclude in-depth assessment by a clinician. Equally, there is increasing emphasis on the n...

Individuals affected by inherited neuromuscular diseases often present with a specific pattern of muscle weakness, which can guide clinicians in genetic investigations and variant interpretation. Nonetheless, more than 50% of cases do not receive a genetic diagnosis. Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with a pa...

Purpose Advancements in genetic testing and analysis have allowed improved identification of the genetic basis of childhood apraxia of speech, a rare speech presentation. This study aimed to understand speech-language pathologists' (SLPs') consideration of incorporation of genetics in clinical practice using a theory-informed qualitative approach....

Objective: To evaluate the association between hCG and adverse pregnancy outcomes. Data sources: Medline, Embase, PubMed and Cochrane were searched in November 2021 using medical subject headings (MeSH) and relevant keywords. Study eligibility criteria: Published full text studies of pregnant women with serum hCG testing between 8-28 week gest...

Purpose Clear understanding of mental health phenotypes and associated socioeconomic, physical health and well-being impacts in adult women with an FMR1 premutation (PM) is needed for counseling and primary healthcare. Methods A questionnaire captured mental health conditions in women with a PM, using lifetime diagnosis and nested psychometric sca...

Aim To better understand parents' beliefs about causation in cerebral palsy (CP) and the emotions related to those beliefs. Method We surveyed 226 parents of children with CP aged 1 to 18 years, recruited from the Victorian Cerebral Palsy Register, to evaluate their beliefs about the causes of CP, including genetic causes, causes specific to their...

This study characterizes the DNA methylation patterns specific to fragile X syndrome (FXS) with a full mutation (FM > 200 CGGs), premutation (PM 55–199 CGGs), and X inactivation in blood and brain tissues at the 3′ boundary of the FMR1 promoter. Blood was analyzed from 95 controls and 462 individuals (32% males) with FM and PM alleles. Brain tissue...

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of di...

We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as...

MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation or OXPHOS system encoded by mitochondrial DNA. We used multi-omics and gene matching to identif...

The low copy tandem repeat area at Xq28 is prone to recurrent copy number gains, including the K/L mediated duplications of 300 kb size (herein described as the K/L mediated Xq28 duplication syndrome). We describe five families, including nine males with K/L mediated Xq28 duplications, some with regions of greater copy number variation (CNV). We su...

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine...

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has b...

Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known ge...

Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and develo...

Speech and language impairment is core in Koolen-de Vries syndrome (KdVS), yet only one study has examined this empirically. Here we define speech, language, and functional/adaptive behaviour in KdVS; while deeply characterising the medical/neurodevelopmental phenotype in the largest cohort to date. Speech, language, literacy, and social skills wer...

Background Despite the increasing number of clinical trials involving children with neurodevelopmental disorders, appropriate and objective outcome measures for behavioral symptoms are still required. Aim This study assessed the agreement between parents' and clinical researchers' ratings of behavioral problem severity in children with fragile X s...

We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndr...

Presentation to ASIEM SIG day about a case of MCAD being diagnosed on carrier screening impacting on management in a patient with Type 1 Diabetes.

Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active‐unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messen...

Background Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. Methods Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2 -only variants (12 loss-of-function, five m...

Background: Use of ICSI has escalated globally. Concerns include: 1) heritability of infertility, 2) effects of poor-quality spermatozoa on offspring health, 3) epigenetic effects of ICSI procedure. Aim: Compare reproductive and metabolic health of ICSI-conceived men to IVF-conceived and spontaneously conceived (SC) controls. Method: This study is...

Background: We have an established cohort of singleton adults conceived by IVF and GIFT born from January 1982 to December 1992, and matched controls conceived without assisted reproduction (non-ART). They have participated in two previous studies: 1) a telephone interview study when aged 21 years on average and 2) a clinical review 6 years later....

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic...

Speech and language impairments are central features of CDK13 -related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and devel...

Study question: Is the metabolic health of men conceived using ICSI different to that of IVF and spontaneously conceived (SC) men? Summary answer: ICSI-conceived men aged 18-24 years, compared with SC controls, showed differences in some metabolic parameters including higher resting diastolic blood pressure (BP) and homeostasis model assessment...

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify mo...

We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndr...

Purpose Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV...

Numerous chronic diseases have a substantial hereditary component. Recent advances in human genetics have allowed the extent of this to be quantified via genome-wide association studies, producing polygenic risk scores (PRS), which can then be applied to individuals to estimate their risk of developing a disease in question. This technology has rec...

Speech and language impairment is core in Koolen-de Vries syndrome (KdVS), yet only one study has examined this empirically. Here we define speech, language, and functional/adaptive behaviour in KdVS; while deeply characterising the medical/neurodevelopmental phenotype in the largest cohort to date. Speech, language, literacy, and social skills wer...

Pathogenic KAT6A variants cause syndromic neurodevelopmental disability. “Speech delay” is reported, yet none have examined specific speech and language features of KAT6A syndrome. Here we phenotype the communication profile of individuals with pathogenic KAT6A variants. Medical and communication data were acquired via standardized surveys and tele...

An expanding range of genetic syndromes are characterized by genome‐wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder‐specif...

Preconception health affects fertility, pregnancy, and future health outcomes but public awareness of this is low. Our aims were to rank priorities for preconception care (PCC), develop strategies to address these priorities, and establish values to guide future work in preconception healthcare in Australia. A Delphi technique involved two rounds o...

Background Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition. Methods Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2 -only variants (13 loss-of-function, 5 missense...

Objectives COVID-19 has led to rapid changes in rehabilitation service provision for young people living with traumatic brain and/or spinal cord injury. The aim of this project was to understand the experiences of rehabilitation service providers during the acute response stage of the COVID-19 pandemic. Specifically, we aimed to identify innovative...

Background: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders in need of innovative 'real-world' outcome measures to evaluate treatment effects. Instrumented gait analysis (IGA) using wearable technology offers a potentially feasible solution to measure "real-world' neurological and motor dysfunction in these...

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we ascertained 70 unrel...

Objective: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus. Methods: Whole-exome and whole-genome sequencing were performed in families linked t...

Speech and language impairments are commonly reported in DYRK1A syndrome. Yet, speech and language abilities have not been systematically examined in a prospective cohort study. Speech, language, social behaviour, feeding, and non-verbal communication skills were assessed using standardised tools. The broader health and medical phenotype was docume...

For three decades, couples at increased risk for a genetic disorder have been offered preimplantation genetic testing (PGT). Simultaneously, PGT for aneuploidy (PGT-A) to improve in vitro fertilization (IVF) outcomes was introduced, but evidence of value-added remains inconsistent. Recently, lower genetic testing costs and shorter turnaround time h...

Numerous studies have investigated the physical health and development of children and adolescents conceived with assisted reproductive technology (ART). Less is known about the quality of life of ART-conceived adults. This study explores the contributions of being conceived with ART and psychosocial cofactors present in young adulthood to the qual...

Aim To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. Method Participants aged 7 years and older with a history of developmental stuttering were recruited. Self‐reported phenotypic data were collected online including stuttering symptomatology, co‐occurring phenotypes, genetic predisposition,...

Objective To determine the semen quality and reproductive hormones of men conceived by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) compared with men conceived without assisted reproductive technology (ART). Design Cohort study. Setting IVF centers in Victoria and the Western Australian Raine Study. Patient(s) Men con...

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we...

Importance Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment. Objective To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at population scale. Design, Setting, and Participants...

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study we...

The scope of noninvasive prenatal testing (NIPT) could expand in the future to include detailed analysis of the fetal genome. This will allow for the testing for virtually any trait with a genetic contribution, including “non-medical” traits. Here we discuss the potential use of NIPT for these traits. We outline a scenario which highlights possible...

Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both ind...

The implementation of genomic testing in pregnancy means that couples have access to more information about their child’s genetic make-up before birth than ever before. One of the resulting challenges is the management of genetic variations with unclear clinical significance. This population-based study will help to close this critical knowledge ga...

The FMR1 premutation (PM:55‐199 CGG) is associated with fragile X‐associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a dau...

Background Research on monogenic forms of autism spectrum disorder (autism) can inform our understanding of genetic contributions to the autism phenotype; yet, there is much to be learned about the pathways from gene to brain structure to behavior. This systematic review summarizes and evaluates research on brain magnetic resonance imaging (MRI) fi...

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Bot...

The study characterised differences in costs associated with raising a child between four rare disorders and examined the associations between these costs with clinical severity. Caregivers of 108 individuals with Prader-Willi, Angelman (AS), Chromosome 15q Duplication and fragile X (FXS) syndromes completed a modified Client Services Receipt Inven...

Aims: To investigate whether second trimester screening (T2MSS) biomarkers are associated with cerebral palsy (CP) and identify CP characteristics associated with abnormal biomarker levels. Method: In this retrospective case-control data linkage study, we linked mothers of 129 singleton CP cases from a population register to their 2TMSS records...

Importance: Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial. Objectives: To identify what has been discovered following the reporting of the first gNBS pilot projects and to provide a summary of key points for the de...

Decisions about genetic testing have traditionally been based on clinical utility and cost, but personal utility is increasingly recognized when assessing the value of testing. Whole exome sequencing (WES) was offered to a population cohort of 106 infants diagnosed with congenital hearing loss. Parents could choose to receive results relating to he...

Aim To delineate the speech and language phenotype of a cohort of individuals with FOXP1‐related disorder. Method We administered a standardized test battery to examine speech and oral motor function, receptive and expressive language, non‐verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together w...

Congenital cataracts are one of the major causes of childhood-onset blindness around the world. Genetic diagnosis provides benefits through avoidance of unnecessary tests, surveillance of extraocular features and genetic family information. In this study, we demonstrate the value of genome sequencing in improving diagnostic yield in congenital cata...