Jenny Patterson

Holt-Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T-box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non-ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long-term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.

BACKGROUND: The value of chromosome microarray (CMA) in the prenatal detection of significant chromosome anomalies is well-established. To guide the introduction of this technique in routine clinical practice, the Joint Committee on Genomics in Medicine developed national UK guidelines for reporting prenatal CMA in 2015. OBJECTIVE: To evaluate the UK experience of utilising prenatal CMA. METHOD: A 36-item survey was distributed to all UK clinical genetics services (n = 23) in March 2019 requesting information pertaining to experience since diagnostic testing commenced and current practice (March 2018 to March 2019). RESULTS: Eighteen UK genetics services currently offer prenatal CMA. A total of 14,554 tests had been performed. A pathogenic copy number variant was identified in 7.8% of tests overall, though the diagnostic rate increased to 8.4% in the final year of the survey. Variants of uncertain significance (VUS) were reported in 0.7% of tests, and 'actionable' incidental findings in 0.12%. CONCLUSION: Diagnostic rate has improved over time, while reporting of VUS has decreased. Reviewing survey responses at a national level highlights variation in testing experience and practice, raising considerations both for future guideline development and implementation of other novel techniques including prenatal whole exome sequencing.

The effects of budgetary changes on midwives' practice environment have raised concerns in many settings. A survey of midwives and student midwives in the UK and Republic of Ireland in 2014 produced 280 responses. Staffing shortages were regarded as underpinning many changes, one of which was that of previously optional 'extra' activities, such as unpaid overtime, becoming mandatory. Shortages were aggravated in less acute areas by the transfer of midwives to more acute settings. One of the fears expressed by midwives was that a permanent change in the culture of midwifery would result. These phenomena are the everyday experiences of practising midwives, but they have failed to be addressed in the documents published by regulatory and review bodies.

My main aim in working as an independent midwife over the last three years has been to provide a level of continuity and stability for the woman and family not always possible within the NHS. While aiming to provide excellent clinical care I also provide up-to-date evidence based information, such as guidelines for women from the Royal College of Obstetrics and Gynaecology (RCOG) or the National Institute for Clinical Excellence (NICE) which enables the woman's choices to be informed. In the course of a woman's care it is frequently necessary to work together with health professionals within the NHS. The following story both exemplified for me the way things can work when we collaborate fully with one another and was also an incredibly positive experience for all involved.

Purpose: We sought to evaluate outcomes for clinical management after a genetic diagnosis from the Deciphering Developmental Disorders study. Methods: = 5010). Clinical notes from regional clinical genetics services notes were reviewed to assess predefined clinical outcomes relating to interventions, prenatal choices, and information provision. Results: Outcomes were recorded for 4237 diagnosed probands (85% of those eligible) from all 24 recruiting centers across the United Kingdom and Ireland. Clinical management was reported to have changed in 28% of affected individuals. Where individual-level interventions were recorded, additional diagnostic or screening tests were started in 903 (21%) probands through referral to a range of different clinical specialties, and stopped or avoided in a further 26 (0.6%). Disease-specific treatment was started in 85 (2%) probands, including seizure-control medications and dietary supplements, and contra-indicated medications were stopped or avoided in a further 20 (0.5%). The option of prenatal/preimplantation genetic testing was discussed with 1204 (28%) families, despite the relatively advanced age of the parents at the time of diagnosis. Importantly, condition-specific information or literature was given to 3214 (76%) families, and 880 (21%) were involved in family support groups. In the most common condition (KBG syndrome; 79 [2%] probands), clinical interventions only partially reflected the temporal development of phenotypes, highlighting the importance of consensus management guidelines and patient support groups. Conclusion: Our results underscore the importance of achieving a clinico-molecular diagnosis to ensure timely onward referral of patients, enabling appropriate care and anticipatory surveillance, and for accessing relevant patient support groups.