505 Beecroft SJ, et al. J Med Genet 2018;55:505–514. doi:10.1136/jmedgenet-2018-105266 REVIEW Genetics of neuromuscular fetal akinesia in the genomics era Sarah Jane Beecroft, 1,2 Marcus Lombard, 1,2 David Mowat, 3 Catriona McLean, 4 Anita Cairns, 5 Mark Davis, 6 Nigel G Laing, 1,2 Gianina Ravenscroft 1,2 Neurogenetics To cite: Beecroft SJ, Lombard M, Mowat D, et al. J Med Genet 2018;55:505–514. 1 Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia 2 Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia 3 Centre for Clinical Genetics, Sydney Children’s Hospital, Sydney, New South Wales, Australia 4 Victorian Neuromuscular Laboratory, Alfred Health, Melbourne, Victoria, Australia 5 Department of Neurology, Lady Cilento Children’s Hospital, Brisbane, Queensland, Australia 6 Neurogenetics Laboratory, Department of Diagnostic Genomics, PP Block, QEII Medical Centre, Nedlands, Western Australia, Australia Correspondence to Dr Gianina Ravenscroft, Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA 6009, Australia; gina.ravenscroft@ uwa.edu.au SJB and ML contributed equally. Received 17 January 2018 Revised 22 March 2018 Accepted 19 April 2018 Published Online First 29 June 2018 ABSTRACT Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders, united by impaired movement in utero. Often, the underlying aetiology is genetic in origin, affecting part of the neuromuscular system. The affordable and high-throughput nature of next- generation DNA sequencing has led to an explosion in disease gene discovery across rare diseases, including fetal akinesias. A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions. More broadly, knowledge of disease genes increasingly allows population-based preconception carrier screening, which has reduced the incidence of recessive diseases in several populations. Despite gains in knowledge of the genetics of fetal akinesia, many families lack a genetic diagnosis. In this review, we describe the developments in Mendelian genetics of neuromuscular fetal akinesia in the genomics era. We examine genetic diagnoses with neuromuscular causes, specifically including the lower motor neuron, peripheral nerve, neuromuscular junction and muscle. INTRODUCTION Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders with the unifying feature of reduced or absent fetal movement, which results in a variety of secondary defects. 1 For simplicity, we will from here on refer to these diseases as fetal akinesias. This group contains several over- lapping entities, ranging in severity from distal arthrogryposis, multiple pterygium syndrome and arthrogryposis multiplex congenita (AMC), to the most severe, fetal akinesia deformation sequence (FADS). 1 Features vary depending on when fetal movement was impaired. The phenotype may be further complicated by abnormalities associated with the underlying cause of the akinesia. However, common features include subcutaneous oedema, fetal hydrops, lung hypoplasia, rocker-bottom feet, craniofacial anomalies (particularly cleft palate, retromicrognathia), intrauterine growth restriction and poor muscle bulk. 1 Landmark studies demon- strated reduced fetal movement is responsible for the main clinical features, highlighting the need for adequate fetal movement in normal development. 2 3 The underlying defect can be genetic or environ- mental. The aetiology is generally categorised into muscular disorders, neurological disorders (central and/or peripheral, and neurometabolic), connective tissue disorders, fetal vascular compromise, uterine space limitations and maternal diseases or drug use. 1 This review is an update from Ravenscroft et al 1 covering discoveries in monogenic fetal akinesia disorders with neuromuscular causes. 1 Specifi- cally, we focus on conditions affecting the lower motor neuron, peripheral nerves, neuromuscular junction (NMJ) and skeletal muscles. As per the 2011 review, restrictive dermopathies and primary brain abnormalities are excluded. However, it is important to note that brain abnormalities are often difficult to distinguish from primary neuromuscular causes of fetal akinesia because the clinical features can overlap considerably. Genes recently associated with central forms of fetal akinesia include PI4KA, PDHA1 and SLC6A9. 4–6 Table 1 summarises new discoveries since the 2011 review. Since 2011, there has been an explosion in disease gene discovery, powered by affordable massively parallel next-generation sequencing (NGS). New genotype–phenotype correlations are blurring the boundaries between what were once considered distinct entities. 7 8 This trend extends beyond fetal akinesia, across neuromuscular diseases as a whole. 8 Defining the genetic and phenotypic spectra of fetal akinesias is significant for patients and clinicians, as it facilitates a genetic diagnosis. 8 9 This is vital, as clinical diagnosis of fetal akinesia disorders mid-ges- tation is especially challenging; ultrasonography has limited diagnostic utility, and clinical information such as intellectual ability is not available. 10–12 Post- natal diagnosis is hampered by the clinical hetero- geneity of the fetal akinesia spectrum. 10 Beyond immediate clinical utility, genetic diagnosis clarifies family genetic implications and allows consider- ation of reproductive options in ‘high risk’ cases (ie, preimplantation genetic diagnosis, prenatal genetic diagnosis). Paediatric precision medicine has the potential to resolve heterogeneity, limit unneces- sary testing and spare parents and patients from the diagnostic odyssey. 13 Rapid NGS-based testing for genetic diseases showed significant success in neonatal and paediatric intensive care units, allowing reduction of morbidity and mortality via precision interventions. 13 14 However, this requires large quantities of high-quality DNA from the affected offspring. Access to sufficient quantity/quality of material is often limited, particularly in cases of fetal demise. 12 An alternative approach is parental exome sequencing, which searches for rare, hetero- zygous variants occurring in the same gene in both parents. Despite being unable to identify de novo variants, this method had an overall success rate of on April 25, 2020 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmedgenet-2018-105266 on 29 June 2018. Downloaded from