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Spectrum of germline pathogenic variants in early-onset breast cancer: a multicentre retrospective study in Malaysia

2026-10-09T07:18:07Z

Title: Spectrum of germline pathogenic variants in early-onset breast cancer: a multicentre retrospective study in Malaysia Authors: Foong Le Hui Abstract: Early-onset breast cancer (EOBC) is an important clinical indication for hereditary cancer assessment, as younger patients with breast cancer (BC) have a higher likelihood of carrying germline cancer predisposition variants compared with unselected BC populations. However, local data on the gene spectrum and diagnostic yield of germline pathogenic/likely pathogenic (P/LP) variants among Malaysian EOBC patients remains limited. In particular, the contribution of non-BRCA cancer predisposition genes, clinicopathological predictors of germline P/LP variants, and the outcomes of different genetic testing approaches is not well characterised. This study aimed to characterise the spectrum of germline P/LP variants, examine their association with clinicopathological characteristics, and compare the diagnostic yield of BRCA-only and multigene panel testing among Malaysian EOBC patients. This multicentre retrospective study included EOBC patients diagnosed at <45 years of age who underwent germline genetic testing between 2020 and 2025. Data were collected from CRM, HKL and Hospital TABTAR. Demographic, clinicopathological, family history and genetic testing data were extracted from medical records. A total of 725 patients were included. Overall, 145 patients (20.0%) carried germline P/LP variants across 14 cancer predisposition genes. BRCA1 was the most frequently identified gene (40.5%), followed by BRCA2 (36.5%), while non-BRCA P/LP variants accounted for 23.0% of positive genetic findings, with PALB2 (5.4%), ATM (4.1%) and TP53 (3.4%) being the most common. In addition, triple-negative breast cancer (TNBC), bilateral BC and positive family history were identified as independent predictors of carrying germline P/LP variants. Diagnostic yield was 23.9% for BRCA-only testing and 19.1% for multigene panel testing. Detection of variant of uncertain significance (VUS) increased with larger panel size, highlighting the importance of careful variant interpretation and genetic counselling. These findings support EOBC as an indication for germline genetic testing and more appropriate referral for genetic counselling and testing.

Secondary findings in whole exome sequencing: prevalence and management

2026-10-09T07:10:08Z

Title: Secondary findings in whole exome sequencing: prevalence and management Authors: Nur Mashitah Mohd Shahrom Abstract: Whole exome sequencing (WES) is a genomic diagnostic tool widely used to identify genetic variants associated with rare diseases and undiagnosed conditions. In addition to diagnosing the primary condition, WES may also generate secondary findings that are unrelated to the primary indication of testing but have important clinical implications. However, data on the prevalence and clinical management of secondary findings in the Malaysian population remain limited. This study aimed to evaluate the prevalence and clinical management of secondary findings identified through WES at Hospital Kuala Lumpur (HKL) and Hospital Tunku Ampuan Besar Tuanku Aishah Rohani, UKM Children's Specialist Hospital (Hospital TABTAR). A retrospective clinical audit was conducted involving 882 patients who underwent WES between January 2021 and March 2026. Of these, 790 patients consented to receive secondary findings and were included in the secondary findings analysis, while 92 patients opted out and were excluded. Data were obtained from medical records, including demographic characteristics, genetic test results, classification of secondary findings according to the American College of Medical Genetics and Genomics (ACMG) guidelines, and clinical management outcomes. Descriptive statistical analyses were performed. Secondary findings were identified in 33 patients among 790 individuals (4.18%), with a total of 28 secondary findings recorded. One patient harboured two distinct secondary findings. Of the variants identified, 13 (46.43%) were classified as pathogenic and 15 (53.57%) as likely pathogenic. The majority of secondary findings involved genes associated with cardiovascular disorders and hereditary cancer syndromes. Clinical management commonly included genetic counselling and specialist referral, although variability was observed in follow-up adherence and cascade screening uptake among family members. This study provides local evidence on the burden and clinical management of secondary findings identified through WES in Malaysia. The findings highlight the importance of structured follow-up pathways, effective genetic counselling, and improved integration of genomic medicine into routine clinical practice to optimise the clinical utility of secondary findings.

Parental perception of Genomic Newborn Screening (GNBS) in a Malaysian tertiary paediatric setting

2026-10-08T04:30:16Z

Title: Parental perception of Genomic Newborn Screening (GNBS) in a Malaysian tertiary paediatric setting Authors: Chin Pei Voon Abstract: Genomic newborn screening (gNBS) is an emerging approach that offers the potential for early identification of genetic conditions beyond those detected through conventional newborn screening. However, evidence regarding parental perceptions on gNBS in Malaysia remains limited. This study aimed to assess parental perspectives, attitudes and acceptance of gNBS and to identify factors associated with willingness to support its implementation. A quantitative cross-sectional survey was conducted among 429 parents attending the paediatric outpatient clinics at Hospital Tunku Ampuan Besar Tuanku Aishah Rohani (Hospital TABTAR). Participants completed a structured self- administered questionnaire following provision of information regarding newborn screening and gNBS. Awareness of gNBS was low, with only 21.0% of parents reporting prior awareness. Nevertheless, most parents supported the implementation of gNBS (74.6%). The most commonly perceived benefits were early and effective treatment (88.1%), timely genetic diagnosis (82.3%) and provision of comprehensive health information (78.3%). Key concerns included anxiety regarding a child's future health (79.5%), financial costs (74.1%) and misinterpretation of genetic results (64.1%). Cost of testing and treatment (86.9%), diseases included in screening (75.4%) and treatment availability (71.9%) were the main factors influencing parental decision- making. Multivariable analysis identified belief in the treatability of genetic diseases (aOR = 1.98, 95% CI: 1.03-3.80, p = 0.039) as the only independent factor associated with support for gNBS. These findings suggest that Malaysian parents are generally receptive towards gNBS despite limited awareness, highlighting the need public education, genetic counselling resources, appropriate governance frameworks to support its implementation.

Exploring genetic discrimination experienced by parents of children with rare diseases in Malaysia: a qualitative study

2026-10-08T04:06:28Z

Title: Exploring genetic discrimination experienced by parents of children with rare diseases in Malaysia: a qualitative study Authors: Siti Aisyah Syamsul Abstract: Background Advances in genetic testing have transformed the landscape of rare disease diagnosis and clinical management. Yet, alongside these benefits, concerns remain regarding genetic discrimination and the broader social consequences of living with a genetic condition. While existing research has focused largely on hereditary cancer syndromes and predictive genetic testing, little is known about how local families affected by rare genetic conditions experience discrimination in everyday life. This study explored the experiences of genetic discrimination among parents of children with rare genetic conditions in Malaysia, including the settings in which discrimination occurred, its impact, coping strategies and recommendations for improving support. Methods A qualitative study design was employed. Semi-structured interviews were conducted with 15 parents of children diagnosed with rare genetic conditions, primarily recruited through the Malaysia Rare Disease Society (MRDS). Data were analysed using Braun and Clarke's reflexive thematic analysis approach. Five major themes: 1) diagnosis and genetic testing experience, 2) genetic discrimination, 3) emotional and social impact, 4) coping strategies, 5) suggestions and unmet needs were identified. Results Participants frequently characterised diagnostic journey as challenging, often involving prolonged periods without clear answers, while genetic testing played a crucial role in establishing diagnosis. Participants reported experiences of discrimination and disadvantage across healthcare, employment, insurance, education and social settings. Insurance-related barriers represented the clearest form of direct discrimination, while experiences in other settings included limited educational accommodations, perceived dismissal of concems within healthcare settings, and social misunderstanding of rare genetic conditions. Some experiences also reflecting disability- related stigma, phenotype-based disadvantage, and structural barriers. These experiences contributed to emotional distress and caregiver burden, while parents responded through advocacy, selective disclosure, and social support. Participants highlighted the need for integrated care, greater professional and public awareness, and stronger financial protection for families affected by rare genetic conditions. Conclusion The findings suggest that experiences of discrimination among rare disease families are closely intertwined with the everyday realities of caregiving and navigating systems that are inadequately prepared to support rare conditions. As one of the first qualitative studies to explore genetic discrimination among rare disease families in Malaysia, the findings highlight the need for greater awareness, equitable access to services, and stronger policy protections, while supporting the implementation of Malaysia's National Policy for Rare Diseases (2025).