Preparing tomorrow's doctors for the genomics era: A nationwide survey of UK medical students.

Introduction: Low confidence in genomics knowledge among clinicians is a major barrier to the integration of genomics into mainstream medicine. Here, we assessed the genomics confidence of UK medical students approaching graduation. Methods: We conducted a web-based nationwide survey of UK medical students in the final 2 years of study where participants rated their confidence in genomics concepts. Results: In total, 145 medical students across 19 medical schools participated. The amount of genomics teaching students reported receiving was positively associated with genomics confidence, with the amount of basic science teaching having the strongest influence. While confidence was high in core genomics principles, such as the difference between DNA, genes and chromosomes (95%), confidence dropped in clinical applications of genomics - only 50% reported a good understanding of the genetic contribution to disease and 28% reported good knowledge of clinically used genomic tests. Overall, 59% reported a poor understanding of variant interpretation; however, over half who reported receiving 'lots' of genomic medicine teaching reported a good understanding of this topic. Conclusion: Gaps in genomics knowledge and drivers in confidence have been identified herein, highlighting the need for improvements in undergraduate genomics education to prepare future doctors to confidently practise in the genomics era.

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

From Beyond the Grave: Use of Medical Information from the Deceased to Guide Care of Living Relatives.

PURPOSE OF REVIEW: In order to inform patients of their genetic risks, access to the medical records and/or stored samples of their relatives is often helpful. We consider some of the obstacles to such access when these relatives are deceased and suggest how they might be navigated. RECENT FINDINGS: We explore an issue first highlighted in 2004 by Lucassen et al. (Br Med J 328:952-953, 2004) and re-evaluate it in the wake of novel technologies and mainstreaming of genomic medicine. We find that it is still an issue in practice despite professional guidelines advocating access to familial information (Joint Committee on Genomics in Medicine 2019) and that the Human Tissue Act 2004 is often wrongly constructed as a reason to block access. Access is often obstructed by failing to adopt the necessary relational concept of autonomy that applies in genetic medicine as reported by Horton and Lucassen (Curr Genet Med Rep 7:85-91, 2019) and by considering confidentiality to be absolute, even after death. In response to a recent legal case about the confidentiality of genetic test results, and their disclosure to family members (ABC v St George's Healthcare NHS Trust 2020), Dove et al. (J Med Ethics 45:504-507, 2019) suggested that a duty to consider the interests of genetic relatives could co-exist alongside a duty of confidentiality to a patient. In this way, healthcare professionals can use professional judgement about the relative value of genetic information to family members. This is equally relevant in accessing deceased relatives' information. A recent systematic review found a high level of acceptability of postmortem use of genetic data for medical research amongst participants and their relatives, and it is reasonable to assume that this acceptability would extend to clinical practice as reported by Bak et al. (Eur J Hum Genet 28:403-416, 2020). SUMMARY: Within clinical practice, access to medical records/samples of deceased relatives is often obstructed unnecessarily, potentially resulting in harm to the living relatives seeking advice. Consent to such access is important but need not be the bureaucratic hurdle that is often imposed.

Inherited 2q23.1 microdeletions involving the MBD5 locus.

BACKGROUND: Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5-Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin. METHODS: This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. RESULTS: Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. CONCLUSIONS: Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought.

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.

Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing.

Metaphyseal dysplasia, Spahr type; missense MMP13 mutations in two Iraqi siblings.

We report on two siblings of Iraqi descent with clinical and radiographic features of metaphyseal dysplasia, Spahr type (MDST), born to consanguineous unaffected parents. Molecular testing confirmed pathogenic mutations in MMP13. We review the considerable overlap between MDST and other related disorders. These cases confirm the phenotypic variability and regressive nature of MDST in addition to suggesting bone fragility as a feature.

Liver abscess within the first week of life in a very low birthweight infant.

Liver abscess is rare in neonates. The present report concerns a preterm neonate with history of antenatal laser ablation therapy (to prevent twin to twin transfusion syndrome), who developed liver abscesses within a few days of life. Conservative treatment with antibiotics led to the normalisation of inflammatory markers, leaving an echogenic (calcified) area in the liver.