KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Therapeutics in paediatric genetic diseases: current and future landscape

There are more than 7,000 paediatric genetic diseases (PGDs) but less than 5% have treatment options. Treatment strategies targeting different levels of the biological process of the disease have led to optimal health outcomes in a subset of patients with PGDs, where treatment is available. In the past 3 decades, there has been rapid advancement in the development of novel therapies, including gene therapy, for many PGDs. The therapeutic success of treatment relies heavily on knowledge of the genetic basis and the disease mechanism. Specifically, gene therapy has been shown to be effective in various clinical trials, and indeed, these trials have led to regulatory approvals, paving the way for gene therapies for other types of PGDs. In this review, we provide an overview of the treatment strategies and focus on some of the recent advancements in therapeutics for PGDs.Published versio

Clinical free text to HPO codes

Leveraging Artificial Intelligence (AI) within the rare disease diagnostic odyssey can facilitate a decrease in diagnostic times and an increase in diagnostic rates. Among the steps involved in the odyssey, this project focused on utilizing AI to automate the standardized capturing of clinical free text into Human Phenotype Ontology (HPO) codes. This research project was conducted at both the KK Women’s and Children’s Hospital (KKH), Singapore and the Rare Care Centre at Perth Children’s Hospital, Western Australia (WA), via the Curtin New Colombo Plan (NCP) Scholarship. The outcome of the project saw the development of a Streamlit web application that utilized two (2) pre-trained AI models – PhenoTagger and PhenoBERT – with a human-in-the-loop design. A case study conducted with ten (10) de-identified clinical reports demonstrated a reduction in the HPO extraction task time from ten (10) to twenty (20) minutes per report to less than five (5) minutes

The Clinical Effects of Fermented Papaya Preparation® (FPP®) on Oxidative Stress in Patients with HbE/ β -Thalassaemia

Background: Red blood cells (RBC) of patients with thalassaemia are under continuous oxidative stress. Fermented papaya preparation® (FPP®) has been shown to have an antioxidative effect and is postulated to reduce the oxidative stress on RBC. Objective: To study the clinical effects of FPP® treatment in patients with HbE/β-thalassaemia on RBC indices, oxidative stress and quality of life scores. Method: Patients with HbE/β-thalassaemia who do not receive regular blood transfusion were included in the study and were given FPP® daily (3gm 2 times a day) for 12 weeks. Peripheral blood samples were obtained at the initiation of the study and at 4-weekly intervals thereafter for a period of 12 weeks. The following parameters were measured: Haemoglobin (Hb), mean corpuscular volume (MCV), reticulocyte count; Oxidation studies: production of reactive oxygen species (ROS) and intracellular glutathione content (GSH), spontaneously and in response to oxidative stress; Quality of life (QoL) at the start and at the end of 12 weeks using health survey questionnaires. Results: Seven patients (5 females and 2 males) were recruited to the study from January 2006 to April 2006. Median age of the study population was 19 years (range 4 to 27yrs). In vitro analyses showed production of significantly less ROS and more GSH following treatment. There was no significant difference in the Hb, MCV, reticulocyte count, clinical parameters or QoL scores. FPP® was well tolerated by all the patients. Conclusion: Although oxidative stress parameters were decreased, FPP® did not have any significant effect on the Hb levels or QoL. Longer studies on larger sample size are required to study the long-term clinical effect of FPP® on clinical parameters in patients with Hb E/β-thalassaemia

Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?

Background: In Western cohorts, the prevalence of incidental findings (IFs) or incidentalome, referring to variants in genes that are unrelated to the patient's primary condition, is between 0.86% and 8.8%. However, data on prevalence and type of IFs in Asian population is lacking. Methods: In 2 cohorts of individuals with genomic sequencing performed in Singapore (total n = 377), we extracted and annotated variants in the 56 ACMG-recommended genes and filtered these variants based on the level of pathogenicity. We then analyzed the precise distribution of IFs, class of genes, related medical conditions, and potential clinical impact. Results: We found a total of 41,607 variants in the 56 genes in our cohort of 377 individuals. After filtering for rare and coding variants, we identified 14 potential variants. After reviewing primary literature, only 4 out of the 14 variants were classified to be pathogenic, while an additional two variants were classified as likely pathogenic. Overall, the cumulative prevalence of IFs (pathogenic and likely pathogenic variants) in our cohort was 1.6%. Conclusion: The cumulative prevalence of IFs through genomic sequencing is low and the incidentalome may not be a significant barrier to implementation of genomics for personalized medicine

Correction to: Family history assessment significantly enhances delivery of precision medicine in the genomics era (Genome Medicine, (2021), 13, 1, (3), 10.1186/s13073-020-00819-1)

10.1186/s13073-021-00916-9Genome Medicine13110

Family history assessment significantly enhances delivery of precision medicine in the genomics era

10.1186/s13073-020-00819-1Genome Medicine131