Breana Cham

Genetic testing in neurology is playing an increasingly important role because of advances in sequencing technologies and the availability of targeted therapeutic options. In Singapore, clinical practice guidelines introduced in 2018 required genetic counseling as a part of clinical genetic testing, and a moratorium implemented in 2021 limited the use of genetic results to determine insurability. In response to these developments, we established a neurogenetics clinic staffed jointly by a neurologist and genetic counselor in September 2020. The objective of this study was to describe the patient population, referral patterns, and factors associated with the decision to undergo genetic testing and evaluate downstream management changes. We conducted a retrospective cohort review of adult patients seen at the Singapore General Hospital neurogenetics clinic between September 2020 and December 2023. Demographic, clinical, and referral data were collected, along with details on testing decisions, type of genetic tests performed, and outcomes. Logistic regression was used to explore demographic or referral factors associated with genetic testing uptake. A total of 164 patients were evaluated; 128 (78%) proceeded with genetic testing. Among the 36 who declined, cost was the predominant reason (72%), followed by insurability concerns (11%), perceived lack of clinical utility (8%), and not wishing to know the diagnosis (8%). Logistic regression showed no significant demographic or referral-related predictors of testing uptake. Of those tested, 38% had pathogenic/likely pathogenic results, 11% had variants of uncertain significance, and 51% had negative results. Clinical management was modified in 90% of those with pathogenic/likely pathogenic results and 79% with uncertain variants. Our findings demonstrate a high uptake of genetic testing in an adult neurogenetics clinic. Financial barriers remain the most significant deterrent. Genetic results had a direct impact on clinical care for most diagnosed patients, highlighting substantial clinical utility. Hence, reducing financial barriers will be essential as genetic testing becomes increasingly central to diagnosis, treatment, and management of neurologic disorders.

Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disorder and a rare cause of urolithiasis due to mutations in APRT (OMIM #102600). APRT deficiency results in increased urinary excretion of 2,8‐dihydroxyadenine (DHA) which can cause urolithiasis and kidney failure. However, with prompt diagnosis, patients with APRT deficiency can be treated with xanthine oxidoreductase inhibitors which decrease urinary DHA excretion and improve outcomes. We report a pair of siblings, an 11‐year‐old brother and his 14‐year‐old sister with compound heterozygous variants c.270del (p.Lys91Serfs*46) and c.484_486del (p.Leu162del) in APRT with variable clinical presentation of APRT deficiency. The brother presented at 17 months of age with urolithiasis and severe acute kidney injury. His elder sister remained well and asymptomatic with normal kidney function and did not develop renal calculi. Brownish disk or sphere‐like crystals with both concentric and radial markings were reported on urine microscopy in the sister on screening. The sister's diagnosis was confirmed with further laboratory evidence of absent red cell lysate APRT activity with corresponding elevated levels of urinary DHA. In conclusion, we identified a novel mutation in the APRT gene in a pair of siblings with greater phenotypic severity in the male. image

Introduction: Assessments drive learning but the influence of the stakes of the assessments on self-regulated (SRL) during and after residency are unknown. As early career specialists (ECS) must continue learning independently, the answer to this is important as it may inform future assessments with the potential to promote life-long learning after graduation. Methods: We utilized constructivist grounded theory to explore the perspectives of eighteen ECS on the influence of stakes of assessments within residency on their SRL during training and in current practice. We conducted semi-structured interviews. Results: We initially set out to examine the influence of the stakes of assessments on SRL during residency and after graduation. However, it was apparent that learners increasingly engaged with others in co-regulated learning (CRL) as the perceived stakes of the assessments increased. The individual learner’s SRL was embedded in CRL in preparation for the various assessments in residency. For low-stakes assessments, the learner engaged in less CRL, taking less cues from others. As stakes increased, the learner engaged in more CRL with peers with similar intellectual level and supervisors to prepare for these assessments. SRL and CRL influenced by assessments in residency had a knock-on effect in clinical practice as ECS in: 1) developing clinical reasoning, 2) improving doctor-patient communication and negotiation skills, and 3) self-reflections and seeking feedback to deal with expectations of self or others. Discussion: Our study supported that the stakes of assessments within residency reinforced SRL and CRL during residency with a continued effect on learning as ECS.

DRG1 is a highly conserved member of a class of GTPases implicated in ribosome biogenesis and translation. The expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes including protein synthesis and cellular proliferation. Using exome sequencing, we identified rare and likely pathogenic germline DRG1 variants including three stop-gained p.Gly54*, p.Arg140*, p.Lys263* and a p.Asn248Phe missense variant. These alleles segregate recessively in four affected individuals from three unrelated families and cause a neurodevelopmental disorder with global developmental delay, microcephaly, short stature and craniofacial anomalies. Using functional assays, we show that these loss-of-function variants: 1) severely disrupt DRG1 mRNA/protein stability in patient-derived fibroblasts, 2) impair it’s GTPase activity in vitro and 3) compromise it’s binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of Drg1 in mice resulted in pre-weaning lethality. Our work highlights the importance of DRG1 GTPase activity for normal development and underscores the significance of translation factor GTPases in human physiology and homeostasis.

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene (NF1) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the NF1 gene have been identified from patients with most of the germline variants are from the Western populations. We found 16 patients (15 Chinese and 1 Asian Indian) who had heterozygous variants in NF1 through targeted next-generation sequencing. There were 15 different variants: 4 frameshift, 4 nonsense, 5 missense, and 2 splice variants. One nonsense variant and three frameshift variants had never been reported in any population or patient database. Twelve of the 16 patients met the NF1 diagnostic criteria, and each was found to have a pathogenic or likely pathogenic variant. Three different missense variants of unknown significance were discovered in the other four patients who did not meet NF1 diagnostic criteria. Our findings add four novel variants to the list of genetic mutations linked to NF1's various clinical manifestations. ^* These two authors are the first coauthors. Received: 25 January 2021 Accepted: 01 September 2021 Publication Date: 19 October 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany