Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Background The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. Methods We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. Results We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants. Conclusions These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms

Assessment of renal functional maturation and injury in preterm neonates during the first month of life

Worldwide, approximately 10% of neonates are born preterm. The majority of preterm neonates are born when the kidneys are still developing; therefore, during the early postnatal period renal function is likely reflective of renal immaturity and/or injury. This study evaluated glomerular and tubular function and urinary neutrophil gelatinase-associated lipocalin (NGAL; a marker of renal injury) in preterm neonates during the first month of life. Preterm and term infants were recruited from Monash Newborn (neonatal intensive care unit at Monash Medical Centre) and Jesse McPherson Private Hospital, respectively. Infants were grouped according to gestational age at birth: ≤28 wk (n = 33), 29–31 wk (n = 44), 32–36 wk (n = 32), and term (≥37 wk (n = 22)). Measures of glomerular and tubular function were assessed on postnatal days 3–7, 14, 21, and 28. Glomerular and tubular function was significantly affected by gestational age at birth, as well as by postnatal age. By postnatal day 28, creatinine clearance remained significantly lower among preterm neonates compared with term infants; however, sodium excretion was not significantly different. Pathological proteinuria and high urinary NGAL levels were observed in a number of neonates, which may be indicative of renal injury; however, there was no correlation between the two markers. Findings suggest that neonatal renal function is predominantly influenced by renal maturity, and there was high capacity for postnatal tubular maturation among preterm neonates. There is insufficient evidence to suggest that urinary NGAL is a useful marker of renal injury in the preterm neonate

Flexible academic support to enhance student retention and success

This paper focuses on the development of Academic Skills Centres (ASCs) at an English University and their impact on the achievement and success of attendees, a high proportion of who are from lower socio-economic groups and Black Minority Ethnic backgrounds. The ASCs aim to meet the needs of students with diverse learning styles and encourage academic skills development through active participation in the learning process. Staffed by both students and lecturers, they adopt flexible approaches and techniques to meet the academic needs of students in a less formal environment than conventional lecturers or seminars. Associations between student success and ASC engagement have been measured through linking attendance records to student profile data using the institutional student record system, enabling analysis of retention, progression, and attainment of users and non-users against a range of profile variables. The results suggest that this is a flexible scheme, able to accommodate the needs of students by creating an environment in which a proactive attitude and dialogue are developed where students are able to enhance their general skills, resulting in greater social mobility through improved retention, attainment and employability

A developmental approach to language acquisition: two case studies

The aim of this article is to revitalize and extend functionalist approaches to language use and language acquisition by utilizing a theory which focuses on general issues of human development. The emphasis here is to show how such developmental considerations enable one to reconstruct a growing child\u27s own efforts to acquire and use a language in increasing accord with cultural demands as to a telos of language development. Two case studies are presented. The first one deals with early phases of language use, in which we analyse subtle ontogenetic changes in the organization and reorganization of personal pronouns referring to the Self. In the second case study, we focus on language modifications during later ontogenesis, analysing the changing functions involving the nominal-pronominal contrast and the contrast between particular tense-aspect markings. It is argued that the ontogenetic changes in both sub-domains are illuminated by exploiting in their analyses Werner & Kaplan\u27s Orthogenetic Principle, in which development is defined in terms of increasing differentiation and hierarchic integration in human functioning. In a final section, we distinguish our Developmental Approach to language acquisition and language use from other functionalist approaches. © 1991, Sage Publications. All rights reserved