The aim of this case series was to assess and characterize cognitive abilities, autistic traits, and adaptive behaviour in Tatton‐Brown‐Rahman syndrome (TBRS). The sample included 18 individuals with ...a clinical and genetic diagnosis of TBRS (11 males, seven females; mean age 17y 7mo, SD 9y 5mo, range 7y 2mo–33y 10mo). The British Ability Scales, Third Edition and the Autism Diagnostic Observation Schedule, Second Edition (ADOS‐2) were administered to all participants. The Social Responsiveness Scale, Second Edition and the Vineland Adaptive Behaviour Scales, Third Edition were completed by a parent/caregiver. The majority of participants (n=15) had intellectual disability and General Conceptual Ability scores ranged from 39 to 76 (mean 53.17, SD 12.13). Participants displayed a profile of better verbal ability compared with non‐verbal reasoning ability and spatial ability. Autistic traits were prevalent and eight participants scored above the cut‐off on the ADOS‐2, although symptoms were less pronounced in older individuals. Adaptive functioning was impaired but commensurate with intellectual ability. Overall, TBRS is associated with an uneven cognitive profile and a high prevalence of autistic traits. This has implications for identifying appropriate services and support that may be beneficial for individuals with TBRS.
What this paper adds
Tatton‐Brown‐Rahman syndrome is associated with intellectual disability and impaired adaptive functioning.
Autistic traits were prevalent within the sample.
Lower intellectual ability and adaptive behaviour were associated with greater severity of autistic traits.
What this paper adds
Tatton‐Brown‐Rahman syndrome is associated with intellectual disability and impaired adaptive functioning.
Autistic traits were prevalent within the sample.
Lower intellectual ability and adaptive behaviour were associated with greater severity of autistic traits.
This article is commented on by Gada on page 894 of this issue.
The growth in genomic testing in healthcare requires a highly trained specialist workforce to ensure evidence based clinical germline variant interpretation. Genetic counselors form a core part of ...the clinical genomics multidisciplinary team (MDT) and represent a growing workforce participating in variant interpretation from data analysis to the patient consultation. Standardized, high‐quality variant interpretation training for Genetic Counselors has historically been ad hoc and variable, with existing programs lacking capacity to reach the entire workforce. To address the requirement for scalable variant interpretation training for genomics healthcare professionals (HCPs), two Massive Open Online Courses (MOOCs) were developed. We analyzed the data from 17 Genetic counselors, as part of an evaluation cohort completing the first run of these MOOCs. Overall genetic counselors enjoyed the courses, felt they were clinically relevant and would recommend them to colleagues. Common challenges amongst the genetic counseling workforces included utilizing relevant databases and finding time in the workday to complete training. These findings suggest MOOCs could be an acceptable option to ensure a consistent and transferrable high standard of training, complimentary to existing curricula. They also hold the potential to facilitate large‐scale education to update the genetic counseling workforce when changes in variant interpretation guidance occur.
The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to ...personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-i.e., precision, or personalized, medicine. In several European countries-such as in England, France and Denmark-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for precision medicine. In other countries-such as Sweden and Germany, with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to precision medicine. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for precision medicine at the regional, national and EU/international levels. We also discuss critical ethical and legal aspects of implementing precision medicine, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, precision medicine represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-i.e., healthcare, academia, policy makers, industry, and patients-must be involved in this system transformation, to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large. This article is protected by copyright. All rights reserved.
PPP2R5D‐related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early‐onset parkinsonism with the PPP2R5D ...p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa‐responsive parkinsonism between the ages of 25 and 40 years. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early‐onset parkinsonism. ANN NEUROL 2020;88:1028–1033
Approach to overgrowth syndromes in the genome era Burkardt, Deepika D.; Tatton‐Brown, Katrina; Dobyns, William ...
American journal of medical genetics. Part C, Seminars in medical genetics,
December 2019, 2019-12-00, 20191201, Letnik:
181, Številka:
4
Journal Article
This introduction to the special issue of AJMG Part C: Overgrowth Syndromes updates the current understanding of overgrowth syndromes. We clarify the terminology associated with overgrowth, review ...some common pathways to overgrowth and present a preliminary classification based on currently known genomic and epigenetic mechanisms. We introduce the articles of this issue—new research and reviews of well‐established and recently described overgrowth syndromes of the brain, body or both.
Abstract Ionotropic glutamate receptors (iGluRs), specifically α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory ...neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1‐4 . Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss‐ or gain‐of‐function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep‐phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well‐established disease‐causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild–severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelopmental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype.
Molecular Mechanisms of Childhood Overgrowth TATTON-BROWN, KATRINA; WEKSBERG, ROSANNA
American journal of medical genetics. Part C, Seminars in medical genetics,
05/2013, Letnik:
163C, Številka:
2
Journal Article
Sotos syndrome is an overgrowth‐intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall ...stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
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