Paediatrics (RCH) - Research Publications

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    Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals
    Morison, LD ; Kennis, MGP ; Rots, D ; Bouman, A ; Kummeling, J ; Palmer, E ; Vogel, AP ; Liegeois, F ; Brignell, A ; Srivastava, S ; Frazier, Z ; Milnes, D ; Goel, H ; Amor, DJ ; Scheffer, IE ; Kleefstra, T ; Morgan, AT (BMJ PUBLISHING GROUP, 2024-01-30)
    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 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.
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    Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder
    Morison, LD ; Van Reyk, O ; Baker, E ; Ruaud, L ; Couque, N ; Verloes, A ; Amor, DJ ; Morgan, AT (Elsevier, 2024-04)
    Pathogenic variants in BRPF1 cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of BRPF1-related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in BRPF1-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 BRPF1 variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in BRPF1-related disorder.
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    Speech and language in DDX3X-neurodevelopmental disorder: A call for early augmentative and alternative communication intervention
    Forbes, EJ ; Morison, LD ; Lelik, F ; Howell, T ; Debono, S ; Goel, H ; Burger, P ; Mandel, J-L ; Geneviève, D ; Amor, DJ ; Morgan, AT (Wiley, 2024-02-29)
    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 pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months-24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.
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    To speak may draw on epigenetic writing and reading: Unravelling the complexity of speech and language outcomes across chromatin-related neurodevelopmental disorders
    St John, M ; Tripathi, T ; Morgan, AT ; Amor, DJ (PERGAMON-ELSEVIER SCIENCE LTD, 2023-09)
    Speech and language development are complex neurodevelopmental processes that are incompletely understood, yet current evidence suggests that speech and language disorders are prominent in those with disorders of chromatin regulation. This review aimed to unravel what is known about speech and language outcomes for individuals with chromatin-related neurodevelopmental disorders. A systematic literature search following PRISMA guidelines was conducted on 70 chromatin genes, to identify reports of speech/language outcomes across studies, including clinical reports, formal subjective measures, and standardised/objective measures. 3932 studies were identified and screened and 112 were systematically reviewed. Communication impairment was core across chromatin disorders, and specifically, chromatin writers and readers appear to play an important role in motor speech development. Identification of these relationships is important because chromatin disorders show promise as therapeutic targets due to the capacity for epigenetic modification. Further research is required using standardised and formal assessments to understand the nuanced speech/language profiles associated with variants in each gene, and the influence of chromatin dysregulation on the neurobiology of speech and language development.
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    The Cost of Raising Individuals with Fragile X or Chromosome 15 Imprinting Disorders in Australia
    Baker, EK ; Arora, S ; Amor, DJ ; Date, P ; Cross, M ; O'Brien, J ; Simons, C ; Rogers, C ; Goodall, S ; Slee, J ; Cahir, C ; Godler, DE (SPRINGER/PLENUM PUBLISHERS, 2023-04-01)
    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 Inventory and participants completed intellectual/developmental functioning and autism assessments. AS incurred the highest yearly costs per individual ($AUD96,994), while FXS had the lowest costs ($AUD33,221). Intellectual functioning negatively predicted total costs, after controlling for diagnosis. The effect of intellectual functioning on total costs for those with AS was significantly different to the other syndromes. The study highlights the significant costs associated with these syndromes, particularly AS, linked with severity of intellectual functioning.
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    Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome
    Baker, EK ; Arpone, M ; Minh, B ; Kraan, CM ; Ling, L ; Francis, D ; Hunter, MF ; Rogers, C ; Field, MJ ; Santa Maria, L ; Faundes, V ; Curotto, B ; Morales, P ; Trigo, C ; Salas, I ; Alliende, AM ; Amor, DJ ; Godler, DE (WILEY, 2023-02-01)
    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 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89-43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R2  = 0.597; p = 1.4 × 10-10 ) and buccal epithelial cells (BEC) (n = 62; R2  = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.
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    Expanding the speech and language phenotype in Koolen-de Vries syndrome: late onset and periodic stuttering a novel feature
    St John, M ; van Reyk, O ; Koolen, DA ; de Vries, BBA ; Amor, DJ ; Morgan, AT (Springer Nature, 2023-05)
    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 were assessed using standardised measures, alongside an in-depth health and medical questionnaire. 81 individuals with KdVS were recruited (35 female, mean age 9y 10mo), 56 of whom harboured the typical 500-650 kb 17q21.31 deletion. The core medical phenotype was intellectual disability (largely moderate), eye anomalies/vision disturbances, structural brain anomalies, dental problems, sleep disturbance, musculoskeletal abnormalities, and cardiac defects. Most were verbal (62/81, 76.5%), while minimally-verbal communicators used alternative and augmentative communication (AAC) successfully in spite of speech production delays. Speech was characterised by apraxia (39/61, 63.9%) and dysarthria (28/61, 45.9%) in verbal participants. Stuttering was described in 36/47 (76.6%) verbal participants and followed a unique trajectory of late onset and fluctuating presence. Receptive and expressive language abilities were commensurate with one another, but literacy skills remained a relative weakness. Social competence, successful behavioural/emotional control, and coping skills were areas of relative strength, while communication difficulties impacted daily living skills as an area of comparative difficulty. Notably, KdVS individuals make communication gains beyond childhood and should continue to access targeted therapies throughout development, including early AAC implementation, motor speech therapy, language/literacy intervention, as well as strategies implemented to successfully navigate activities of daily living that rely on effective communication.
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    Feasibility of wearable technology for 'real-world' gait analysis in children with Prader-Willi and Angelman syndromes
    Kraan, CM ; Date, P ; Rattray, A ; Sangeux, M ; Bui, QM ; Baker, EK ; Morison, J ; Amor, DJ ; Godler, DE (WILEY, 2022-08)
    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 groups. METHODS: Children (50% female; 6-16 years) diagnosed with PWS (n = 9) and AS (n = 5) completed 'real-world' IGA assessments using the Physilog®5 wearable. PWS participants completed a laboratory assessment and a 'real-world' long walk. The AS group completed 'real-world' caregiver-assisted assessments. Mean and variability results for stride time, cadence, stance percentage (%) and stride length were extracted and compared across three different data reduction protocols. RESULTS: The wearables approach was found to be feasible, with all participants able to complete at least one assessment. This study also demonstrated significant agreement, using Lin's concordance correlation coefficient (CCC), between laboratory and 'real-world' assessments in the PWS group for mean stride length, mean stance % and stance % CV (n = 7, CCC: 0.782-0.847, P = 0.011-0.009). CONCLUSION: 'Real-world' gait analysis using the Physilog®5 wearable was feasible to efficiently assess neurological and motor dysfunction in children affected with PWS and AS.
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    ISPD 2021 debate - All in vitro fertilization cycles should involve pre-implantation genetic testing to improve fetal health and pregnancy outcomes
    Wilkins-Haug, L ; Amor, DJ ; Savulescu, J (WILEY, 2022-07)
    For 3 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 have reinvigorated PGT-A. Additionally, a shift from blastomere (day 3) to blastocyst (day 5) transfer and embryo freezing advances support PGT without the time constraints of immediate transfer. PGT-A transformed from a time-constrained analysis of 1-2 cells to an "add on" study for all IVF. But should it be offered to all IVF patients? And if not, under what conditions? Pre-debate polling found 64% opposed to PGT for all IVF cycles with concerns voiced about cost, informed consent, and a "slippery slope". Leaving aside the inconsistent evidence of IVF improvement whether measured as miscarriage or livebirths with PGT-A, the debaters grappled with patient and provider desires versus the ethical concerns for the unborn child. However, the audience was not swayed; two thirds remained opposed to PGT for all IVF cycles.
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    Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability
    Francis, DI ; Stark, Z ; Scheffer, IE ; Tan, TY ; Murali, K ; Gallacher, L ; Amor, DJ ; Goel, H ; Downie, L ; Stutterd, CA ; Krzesinski, EI ; Vasudevan, A ; Oertel, R ; Petrovic, V ; Boys, A ; Wei, V ; Burgess, T ; Dun, K ; Oliver, KL ; Baxter, A ; Hackett, A ; Ayres, S ; Lunke, S ; Kalitsis, P ; Wall, M (SPRINGERNATURE, 2023-05)
    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 syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 individuals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in individuals with syndromic ID, we recommend it as a first-tier testing in this group.