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Basal progenitors (BPs), including intermediate progenitors and basal radial glia, are generated from apical radial glia and are enriched in gyrencephalic species like humans, contributing to neuronal expansion. Shortly after generation, BPs delaminate towards the subventricular zone, where they further proliferate before differentiation. Gene expression alterations involved in BP delamination and function in humans are poorly understood. Here, we study the role of LGALS3BP, so far known as a cancer biomarker, which is a secreted protein enriched in human neural progenitors (NPCs). We show that individuals with LGALS3BP de novo variants exhibit altered local gyrification, sulcal depth, surface area and thickness in their cortex. Additionally, using cerebral organoids, human fetal tissues and mice, we show that LGALS3BP regulates the position of NPCs. Single-cell RNA-sequencing and proteomics reveal that LGALS3BP-mediated mechanisms involve the extracellular matrix in NPCs’ anchoring and migration within the human brain. We propose that its temporal expression influences NPCs’ delamination, corticogenesis and gyrification extrinsically. Basal progenitors are enriched in gyrencephalic species like humans contributing to neuronal expansion. Here the authors show that LGALS3BP de novo variants are related to reduced cortical complexity and area in humans and that LGALS3BP regulates neural progenitor position in organoids, human fetal tissue and mice.

Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2 . QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease. Defects in growth hormone (GH) action account for a substantial percentage of endocrine causes of growth failure. Here, the authors report that QSOX2 deficiency modulates human growth by impairing GH-STAT5B downstream activities and mitochondrial dynamics, contributing to multi-system dysfunction.

Richard Trembath and colleagues show that mutations in NOTCH2 cause Hajdu-Cheney syndrome, a multisystem disorder marked by severe and progressive bone loss. The mutations are predicted to result in elevated NOTCH2 signaling. We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype–phenotype correlations. Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype–phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes. Genet Med18 11, 1143–1150.

To the Editor: Tuberous sclerosis is an autosomal dominant disorder characterized by hamartomatous growths in many organs and caused by inherited mutations of the TSC1 or TSC2 gene. Acquired (somatic) mutations of either gene occur within pathologic cells in patients with sporadic lymphangioleiomyomatosis. Renal angiomyolipomas occur in both disorders, resulting in substantial morbidity and mortality. 1 The proteins TSC1 and TSC2 regulate signaling through the mammalian target of rapamycin (mTOR) pathway to control processes including growth, cell-cycle progression, apoptosis, and autophagy. Constitutive activation of mTOR and its downstream targets occurs in lesions associated with tuberous sclerosis or lymphangioleiomyomatosis, suggesting that mTOR . . .

Objectives(1) To explore professional and lay stakeholder views on the design and delivery of services in the area of consanguinity and genetic risk. (2) To identify principles on which there is sufficient consensus to warrant inclusion in a national guidance document. (3) To highlight differences of opinion that necessitate dialogue. (4) To identify areas where further research or development work is needed to inform practical service approaches.DesignDelphi exercise. Three rounds and one consensus conference.SettingUK, national, web-based and face-to-face.ParticipantsRecruitment via email distribution lists and professional networks. 42 participants with varied professional and demographic backgrounds contributed to at least one round of the exercise. 29 people participated in statement ranking across both rounds 2 and 3.ResultsOver 700 individual statements were generated in round 1 and consolidated into 193 unique statements for ranking in round 2, with 60% achieving 80% or higher agreement. In round 3, 74% of statements achieved 80% or higher agreement. Consensus conference discussions resulted in a final set of 148 agreed statements, providing direction for both policy-makers and healthcare professionals. 13 general principles were agreed, with over 90% agreement on 12 of these. Remaining statements were organised into nine themes: national level leadership and coordination, local level leadership and coordination, training and competencies for healthcare and other professionals, genetic services, genetic literacy, primary care, referrals and coordination, monitoring and evaluation and research. Next steps and working groups were also identified.ConclusionsThere is high agreement among UK stakeholders on the general principles that should shape policy and practice responses in this area: equity of access, cultural competence, coordinated inter-agency working, co-design and empowerment and embedded evaluation. The need for strong national leadership to ensure more efficient sharing of knowledge and promotion of more equitable and consistent responses across the country is emphasised.

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

This document is written on behalf of the two professional bodies in the United Kingdom that represent genetic counsellors (the Association of Genetic Nurses and Counsellors) and clinical geneticists (the Clinical Genetics Society) and aims to support multidisciplinary working of these professional groups highlighting within a quick-reference format, areas of shared practice and the distinctions between role profiles for a Consultant Clinical Geneticist, Principal/Consultant Genetic Counsellor and the new support role that we have termed ‘Genomic Associate’, see AGNC career structure [1]. This builds on published documents that articulate the scope of practice of the clinical genetics workforce [2] and specifically the genetic counsellor [3] and clinical geneticist [4] roles.

Background and AimNICE guidelines recommend universal testing of newly diagnosed colorectal and endometrial cancer for Lynch syndrome (LS), however there is strong evidence of variation in delivery of these guidelines by clinical services. In England, through 7 regional Genomics Medicine Service Alliances (GMSA), a transformation project aims to establish robust pathways to improve guideline compliance (https://www.norththamesglh.nhs.uk/national-gmsa-transformation-project-lynch-syndrome/).MethodA national oversight group was formed in May 2021, with membership drawn from 21 sub-regional Cancer Alliances (CA) and 7 GMSA, charities and other stakeholders. Each CA was tasked with identifying and supporting a responsible ‘Lynch syndrome champion’ within each local cancer team, and we performed a baseline survey to identify barriers to the testing pathway. Workforce training focused on overcoming barriers to testing, identification of eligible patients and mainstreamed constitutional gene testing. Training is delivered via online modules (https://rmpartners.nhs.uk/lynch-syndrome-early-diagnosis-pathway-colorectal-cancer/), workshops, and face-to-face peer-support and co-consultation. Data analysis is performed in conjunction with the National Disease Registration Service (NDRS), and includes clinicopathological data for all cancer patients diagnosed across England, including somatic and constitutional testing outcomes.ResultsBaseline data from NDRS and from the survey demonstrates that although cancer teams self-reported that 71% offer universal testing for LS, in 2019 only 41% of colorectal cancer patients received any form of index tumour ‘mismatch repair ‘(MMR) testing, data which is available on an open access dashboard ‘cancerstats2’. By late 2022 this figure has increased to colorectal and endometrial tumour mismatch repair testing on the Lynch testing pathway from 43% to 91% nationally for CRC (and from 19% to 89% for endometrial cancer), equally across all geographies in England. Lynch champions have been identified in 195 local cancer teams, and LS nurses appointed in each GMSA to support workforce development, along with regional expert networks. 66 new mainstreaming services have been developed within cancer teams, offering genetic testing locally without referral to clinical genetics services. Subgroups have been established in primary care, nursing, pathology, training, and to pilot testing in other Lynch-related tumour types. Each GMSA has identified LS patients diagnosed via their service, used to ascertain 6750 people with LS for a Nationally coordinated screening programme from 2023, and the development of a National LS Registry.ConclusionsThis ongoing transformational project is supported by high levels of engagement across stakeholders in England. Despite barriers, significant quality improvement has been implemented, facilitating systematic delivery of universal testing for LS nationally, with reduction in variation in care.

Purpose Diagnosis of genetic disorders is hampered by large numbers of variants of uncertain significance (VUSs) identified through next-generation sequencing. Many such variants may disrupt normal RNA splicing. We examined effects on splicing of a large cohort of clinically identified variants and compared performance of bioinformatic splicing prediction tools commonly used in diagnostic laboratories. Methods Two hundred fifty-seven variants (coding and noncoding) were referred for analysis across three laboratories. Blood RNA samples underwent targeted reverse transcription polymerase chain reaction (RT-PCR) analysis with Sanger sequencing of PCR products and agarose gel electrophoresis. Seventeen samples also underwent transcriptome-wide RNA sequencing with targeted splicing analysis based on Sashimi plot visualization. Bioinformatic splicing predictions were obtained using Alamut, HSF 3.1, and SpliceAI software. Results Eighty-five variants (33%) were associated with abnormal splicing. The most frequent abnormality was upstream exon skipping (39/85 variants), which was most often associated with splice donor region variants. SpliceAI had greatest accuracy in predicting splicing abnormalities (0.91) and outperformed other tools in sensitivity and specificity. Conclusion Splicing analysis of blood RNA identifies diagnostically important splicing abnormalities and clarifies functional effects of a significant proportion of VUSs. Bioinformatic predictions are improving but still make significant errors. RNA analysis should therefore be routinely considered in genetic disease diagnostics.