Prospective parents' views on reproductive genetic carrier screening: "You know better, you do better".

Reproductive genetic carrier screening (RGCS) allows screening for hundreds of autosomal recessive and X-linked conditions. Multiple clinical professional bodies recommend that RGCS be offered to all prospective parents. There is some research into attitudes to targeted carrier screening for conditions common in specific populations.

Automated Deep Learning-based Segmentation of the Dentate Nucleus Using Quantitative Susceptibility Mapping MRI.

Purpose To develop a dentate nucleus (DN) segmentation tool using deep learning (DL) applied to brain MRI-based quantitative susceptibility mapping (QSM) images. Materials and Methods Brain QSM images from healthy controls and individuals with cerebellar ataxia or multiple sclerosis were collected from nine different datasets (2016-2023) worldwide for this retrospective study (ClinicalTrials.gov Identifier: NCT04349514).

Assessment of Placental Chromosomal Mosaicism during Prenatal Cell-Free DNA Screening Refines Positive Predictive Values for Fetal Trisomy.

Background: Confined placental mosaicism can cause false-positive prenatal cell-free DNA (cfDNA) screening results, thereby reducing the positive predictive value (PPV) of the test. We sought to investigate how PPVs for the common fetal trisomies can be refined based on the presence or absence of chromosomal mosaicism in cfDNA sequencing data.

Methods: The study cohort included singleton pregnancies tested between March 2019 and December 2021.

Revising the reproductive story: psychosocial and reproductive impacts 12 months after reproductive genetic carrier screening.

The responsible implementation of reproductive genetic carrier screening (RGCS) involves understanding the long-term psychosocial and reproductive impacts of results. This mixed-methods study examined these impacts within 'Mackenzie's Mission', an Australia-wide study that offered couple-based RGCS for >1280 genes to 10,000 reproductive couples. Data from participant surveys completed at enrolment and 12 months post-result were analysed.

Comprehensive Characterisation of the RFC1 Repeat in an Australian Cohort.

RFC1-related disease, which includes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), is a late-onset neurodegenerative disorder primarily caused by biallelic AAGGG repeat expansions (RE) in RFC1. The RFC1 locus is highly polymorphic, with multiple pathogenic and non-pathogenic repeat motifs identified. This study aimed to characterise the structure of the RFC1 repeat and determine the pathogenic allele frequency in an Australian cohort.

Haemochromatosis Genotypes and Incident Dementia in a Prospective Study of Older Adults.

Background And Objectives: Variants in the homeostatic iron regulator () gene are prevalent among individuals of European ancestry and have been linked to an increased risk of dementia. This study aimed to evaluate the effects of p.Cys282Tyr and p.

Correction: A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

[This corrects the article DOI: 10.1371/journal.pone.

Effect of creatine monohydrate on motor function in children with facioscapulohumeral muscular dystrophy: A multicenter, randomized, double-blind placebo-controlled crossover trial.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive muscle disease with no available disease-modifying therapy. Creatine monohydrate (CrM) has been shown to improve muscle strength in individuals with muscular dystrophies but has not been tested in young people with FSHD. This study aimed to explore the efficacy of CrM on motor function in children with FSHD.

Neuroimaging Biomarkers for Friedreich Ataxia: A Cross-Sectional Analysis of the TRACK-FA Study.

Objective: We aimed to quantify differences in the brain and spinal cord between Friedreich ataxia and controls, stratified by age and disease stage, including for the first time in young children.

Methods: TRACK-FA is the largest prospective, longitudinal, multi-modal neuroimaging study in Friedreich ataxia to date. We assessed individuals with Friedreich ataxia and controls, 5 to 42 years, at 7 sites across 4 continents.

Correction: A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

[This corrects the article DOI: 10.1371/journal.pone.

A global perspective on research advances and future challenges in Friedreich ataxia.

Friedreich ataxia (FRDA) is a rare multisystem, life-limiting disease and is the most common early-onset inherited ataxia in populations of European, Arab and Indian descent. In recent years, substantial progress has been made in dissecting the pathogenesis and natural history of FRDA, and several clinical trials have been initiated. A particularly notable recent achievement was the approval of the nuclear factor erythroid 2-related factor 2 activator omaveloxolone as the first disease-specific therapy for FRDA.

A prospective trial comparing programmable targeted long-read sequencing and short-read genome sequencing for genetic diagnosis of cerebellar ataxia.

The cerebellar ataxias (CAs) are a heterogeneous group of disorders characterized by progressive incoordination. Seventeen repeat expansion (RE) loci have been identified as the primary genetic cause and account for >80% of genetic diagnoses. Despite this, diagnostic testing is limited and inefficient, often utilizing single gene assays.

Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.

Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively.

Offering reproductive genetic carrier screening for cystic fibrosis, spinal muscular atrophy and fragile X syndrome: Views of Victorian general practitioners.

Background And Objectives: The Royal Australian College of General Practice recommends that all women contemplating pregnancy or in early pregnancy should be offered reproductive genetic carrier screening (RGCS). In November 2023, a new Medicare item number was introduced for RGCS to detect cystic fibrosis (CF), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) carrier status. The role of general practice in offering RGCS is recognised as being of crucial importance, but only a minority of general practitioners (GPs) are offering such screening.

Considering severity in the design of reproductive genetic carrier screening programs: screening for severe conditions.

Reproductive genetic carrier screening (RGCS) provides information about people's chance of having children with certain genetic conditions, to inform reproductive decision making. RGCS at population scale requires a robust and streamlined program that is purposively designed and formally implemented to ensure equity and consistency. There are many considerations in selecting conditions, genes and variants for inclusion in RGCS, with severity of the genetic condition a key criterion.

Nationwide, Couple-Based Genetic Carrier Screening.

Background: Genomic sequencing technology allows for identification of reproductive couples with an increased chance, as compared with that in the general population, of having a child with an autosomal recessive or X-linked genetic condition.

Methods: We investigated the feasibility, acceptability, and outcomes of a nationwide, couple-based genetic carrier screening program in Australia as part of the Mackenzie's Mission project. Health care providers offered screening to persons before pregnancy or early in pregnancy.

Offering complex genomic screening in acute pediatric settings: Family decision-making and outcomes.

Purpose: Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences.

Goal-Directed Rehabilitation Versus Standard Care for Individuals with Hereditary Cerebellar Ataxia: A Multicenter, Single-Blind, Randomized Controlled Superiority Trial.

Objective: Rehabilitation is thought to reduce ataxia severity in individuals with hereditary cerebellar ataxia (HCA). This multicenter, randomized controlled superiority trial aimed to examine the efficacy of a 30-week goal-directed rehabilitation program compared with 30 weeks of standard care on function, ataxia, health-related quality of life, and balance in individuals with an HCA.

Methods: Individuals with an autosomal dominant or recessive ataxia (aged ≥15 years) were enrolled at 5 sites in Australia.

The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses.

Purpose: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.

Methods: A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.