Victorian Clinical Genetics Services

Niemann-Pick disease type C (NP-C) is the fifth most prevalent lysosomal disorder in Australia. Diagnostic delay is common, impacted by disease heterogeneity, limited awareness within clinical gateway services and exclusion from state-based newborn screening programmes. A formal diagnosis, once established, places a substantial burden on the whole family, the negative impact of which is far-reaching. A clear understanding of diagnostic pathways and management objectives in NP-C is critical for optimal care. To develop an Australian standard of care for individuals diagnosed with NP-C and their families, reflecting international best practice and tailored to the Australian healthcare system. The Australian NPC Disease Foundation Inc. convened a national, multidisciplinary collaboration including NP-C treating clinicians, allied health professionals and a community advisory group. Using an iterative consensus approach, published international guidance statements were reviewed, ratified, excluded or modified to align with the Australian context. Consensus outputs included a diagnostic algorithm, a multidisciplinary care framework and management-centred management statements. The collaborative process resulted in a unified Australian standard of care for NP-C. This framework incorporates the carer perspective, emphasises shared decision-making and situates NP-C within the broader context of 'childhood dementias.' Consensus statements provide practical, evidence-aligned guidance on early recognition, diagnostic referral pathways and multidisciplinary management throughout disease progression. This initiative represents the first Australia-specific standard of care for NP-C. It is hoped that adoption of the framework will lead to improved experiences for Australians living with NP-C and their carers as they navigate the healthcare setting.

A false-positive cell-free DNA prenatal screening result may arise from confined placental mosaicism, however, the frequency and obstetrical ramifications of such cases are poorly understood. This study aimed to assess the prevalence of confined placental mosaicism among pregnancies with false-positive cell-free DNA results and the associated obstetrical outcomes. This was a prospective, matched-cohort study with a 1:2 ratio of cases with false-positive cell-free DNA results and controls with low-risk cell-free DNA results that were matched by maternal age and body mass index. Participants were recruited between November 2022 and March 2025 at Monash Health and Monash Ultrasound for Women in Melbourne, Australia. Cytogenetic testing was conducted on 4 biopsies per placenta to investigate confined placental mosaicism. The cases and matched controls were compared using trio matching identifiers as random effect in conditional logistic regression and linear mixed-effects modelling. A total of 60 cases with false-positive cell-free DNA results were matched with 120 controls. Confined placental mosaicism was observed in 20 of the 60 cases (33.3%) and in none of the controls. The prevalence of confined placental mosaicism was highest among those with rare autosomal trisomy (57.9%; 11/19) and monosomy X (75.5%; 3/4) results. Confined placental mosaicism was also observed following common autosomal trisomy results (21.4%; 3/14) and subchromosomal copy number variants (15.8%; 3/19). The median birth weight percentile was significantly lower among instances of confirmed confined placental mosaicism (20.1; interquartile range, 9.9-48.5) than among matched controls (43.5; interquartile range, 17.1-66.1; P=.049); however, there were no statistically significant increases in small-for-gestational-age neonates or other adverse pregnancy outcomes. Confined placental mosaicism is a frequent contributor to false-positive cell-free DNA results, most often for monosomy X and rare autosomal trisomy results. Although the birth weight median percentiles were lower, the outcomes of cell-free DNA-detected confined placental mosaicism in this average-risk cohort were predominantly favorable. VIDEO ABSTRACT.

ABSTRACTSuccinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ALDH5A1, encoding the mitochondrial enzyme SSADH. This enzyme catalyses the conversion of succinic semialdehyde to succinic acid in the γ‐aminobutyric acid (GABA) degradation pathway. SSADH deficiency leads to the accumulation of neurotoxic metabolites, including γ‐hydroxybutyrate (GHB), and presents with developmental delay, hypotonia, ataxia, seizures, behavioral disturbances, and intellectual disability. We report a 10‐month‐old Caucasian male with global developmental delay, central hypotonia, and delayed motor milestones. He presented acutely with left‐sided hemiplegia following irritability and vomiting. Brain MRI showed bilateral (right > left) T2 hyperintensities and diffusion restriction in the globus pallidus. Urine organic acid analysis via gas chromatography–mass spectrometry revealed markedly elevated 4‐hydroxybutyric acid and 4,5‐dihydroxyhexanoic lactone, pathognomonic for SSADH deficiency. Molecular testing identified compound heterozygous ALDH5A1 variants: c.278G>T p.(Cys93Phe) and c.612G>A p.(Trp204*), both previously reported as pathogenic. Parental segregation confirmed trans configuration. Three weeks postillness, he developed focal seizures, which have remained well controlled on levetiracetam. His seizure onset in infancy is notably earlier than the typical early childhood onset (~9 years) reported in SSADH deficiency. This case expands the phenotypic spectrum of SSADH deficiency to include metabolic stroke as a presenting feature in infancy and highlights the importance of early recognition and molecular confirmation to guide management and emerging therapeutic strategies.

The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.

We report the first prenatal diagnosis of a de novo WBP11 variant in a fetus with growth restriction and structural brain anomalies. The case highlights the challenges of counselling with a new and evolving gene-disease association.

Abstract This book has the lofty aim of defining the discipline of “clinical chromosomology.” The wide range of constitutional human chromosome abnormality is documented in considerable detail, and alongside this, the counseling issues that arise for the individuals and families in which these abnormalities have been identified. The classical understanding of chromosomal pathology that evolved in the latter half of the 20th century is reviewed: that is, the well-known trisomies, deletions, and duplication syndromes, and ways in which these may arise de novo, or occur in the setting of a parental chromosome rearrangement. The remarkable advances of this 21st century have demanded the addition of much new material, as the methodology of chromosome analysis has moved largely (not entirely) from microscopy to the molecular approach, and concomitantly, the understanding of the range of the clinical applicability of chromosomal pathology has widened. Developments in prenatal diagnosis have allowed population-level testing to be offered on the basis of a simple blood test. The ability to test the chromosomes of the embryo before implantation, which has been developed only since the turn of the century, has now become a routinely applied procedure, changing the face of how many “translocation couples” deal with the desideratum of having a child with normal chromosomes. This book goes beyond a documentation of chromosome abnormality: it seeks to take a holistic view, looking at the ways in which people and families can come to terms with the chromosomal cards Nature has dealt them.

ABSTRACTBackgroundTetrasomy 9p is a rare chromosomal disorder with distinct clinical features, but wide phenotypic variability. Historically, tetrasomy 9p has been detected by conventional cytogenetic analysis, but newer technologies such as non‐invasive prenatal testing (NIPT) and chromosome microarray (CMA) allow the identification of cases that would previously have gone undetected. Here we describe a girl with a mosaic isodicentric chromosome 9 (idic(9)), ascertained through NIPT, but with diagnosis not confirmed until after birth.MethodsChromosomal microarray (CMA) was performed on DNA extracted from saliva, buccal and blood samples from a clinically well newborn to confirm abnormal prenatal findings. Subsequent conventional G‐banded analysis was performed on stimulated T‐lymphocyte culture following diagnosis of mild speech delay and hearing loss.ResultsCopy number gain at 9p24.3q22.32 was identified on CMA in three independent samples. G‐banded analysis subsequently identified a supernumerary isodicentric chromosome 9 in one out of 105 cells examined, with breakpoints at 9p24 and 9q22.3, representing a partial tetrasomy of chromosome 9.ConclusionTetrasomy 9p has wide phenotypic variability due to mosaicism. This unusually mild case of tetrasomy 9p would have almost certainly gone undetected prior to the implementation of NIPT and CMA. This report highlights the value of reporting cases ascertained through high‐resolution technologies to facilitate early diagnosis and prognosis and enable a better understanding of this condition through precise breakpoint mapping.