Oncologist-led BRCA counselling improves access to cancer genetic testing in middle-income Asian country, with no significant impact on psychosocial outcomes.

BACKGROUND: Identifying patients with BRCA mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming. METHODS: The Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer. RESULTS: Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1 or BRCA2, and there was no difference between psychosocial measures for carriers in both arms. CONCLUSION: The MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.

Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy.

Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5 encoding an RNA-binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss-of-function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole-exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G > A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy/hypoplasia.

Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce. METHODS: This is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients. RESULTS: The patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia - 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified. CONCLUSIONS: All the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.

Novel complex re-arrangement of ARG1 commonly shared by unrelated patients with hyperargininemia.

BACKGROUND: Hyperargininemia is a very rare progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. Until now, some mutations were reported worldwide and none of them were of Southeast Asian origins. Furthermore, most reported mutations were point mutations and a few others deletions or insertions. OBJECTIVE: This study aims at identifying the disease-causing mutation in the ARG1 gene of Malaysian patients with hyperargininemia. METHODOLOGY: We employed a series of PCR amplifications and direct sequencing in order to identify the mutation. We subsequently used quantitative real-time PCR to determine the copy number of the exons flanking the mutation. We blasted our sequencing data with that of the reference sequence in the NCBI in order to obtain positional insights of the mutation. RESULTS: We found a novel complex re-arrangement involving insertion, inversion and gross deletion of ARG1 (designated g.insIVS1+1899GTTTTATCAT;g.invIVS1+1933_+1953;g.delIVS1+1954_IVS2+914;c.del116_188;p.Pro20SerfsX4) commonly shared by 5 patients with hyperargininemia, each originating from different family. None of the affected families share known relationship with each other, although four of the five patients were known to have first-cousin consanguineous parents. CONCLUSION: This is the first report of complex re-arrangement in the ARG1. Further analyses showing that the patients have shared the same geographic origin within the northeastern part of Malaysia prompted us to suggest a simple molecular screening of hyperargininemia within related ethnicities using a long-range PCR.