De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.

What are the novel findings of this work?In this preliminary cohort study, the National Health Service (NHS) England R21 prenatal exome sequencing pathway provided a unifying genetic diagnosis in over 50% of preselected cases with a structural anomaly on prenatal ultrasound. What are the clinical implications of this work?Prenatal exome sequencing using the NHS England R21 pathway can provide diagnostic information in fetuses with a structural malformation. It is important to monitor fetal phenotype throughout the pregnancy and re-evaluate the phenotype postnatally when interpreting prenatal exome sequencing findings to optimize the clinical impact that is already evident from this emerging genomic technology.

Objective: Recent evidence suggests that high cortisol concentrations are associated with increased morbidity and mortality in very low birth weight (VLBW) infants. Neonatal illness severity and mortality risk scores are reliable in predicting morbidity and mortality. The objectives were (i) to assess the correlation between serum cortisol levels and clinical assessment of multi-organ dysfunction/illness severity scores (CRIB II, SNAPPE-II and neonatal multiple organ dysfunction score (NEOMOD)) in first 24 h in VLBW infants and (ii) to assess the relationship between surrogates of end organ blood flow and serum cortisol levels.Study Design: A prospective observational cohort study. Neonates with birth weight <1500 g were eligible for enrollment. Echocardiography evaluation of superior vena cava (SVC) flow was carried out in the first 24 h life. Cortisol levels were measured simultaneously and appropriate clinical scores were calculated.Result: A total of 54 VLBW neonates were enrolled following parental consent. Two patients were excluded because of congenital malformations. In 14 babies the cortisol value was not simultaneously obtained. The mean birth weight was 1.08 kg, mean gestational age was 27.8 weeks. There was a significant correlation between cortisol and NEOMOD score (P ¼ 0.006). There was no correlation between cortisol and CRIB II score (P ¼ 0.34), SVC flow (P ¼ 0.49) and mean arterial blood pressure respectively (P ¼ 0.35). Conclusion:There was no correlation between SVC flow and cortisol values or between cortisol and mean blood pressure values. There was a significant correlation between cortisol levels and neonatal organ dysfunction score evaluated suggesting that stressed VLBW infants do mount a cortisol response. Keywords: VLBW; neonate; cortisol; superior vena cava; blood pressure; illness severity score IntroductionThe immediate postnatal period in very low birth weight (VLBW) infants is frequently complicated by hypotension and low end-organ flow. Superior vena cava (SVC) flow has proven to be a useful marker of systemic blood flow, 1 but is not easily obtained at the bedside. Blood pressure values are readily available at the bedside and hypotension has been associated with adverse short-term and long-term outcome.2,3 A number recent studies have focused on evaluating the role of hydrocortisone therapy in hypotension and suspected adrenocortical insufficiency in the sick preterm infants during the early course of life.

MDK was an investigator and grant holder as part of the Prenatal Assessment of Genomes and Exomes (PAGE) study. This represents research commissioned by the Health Innovation Challenge Fund (HICF-R7-396), a parallel funding partnership between the Department of Health and the Wellcome Trust. The views expressed in this publication are those of the author and not necessarily those of the Department of Health or the Wellcome Trust. MDK is also a member of the RCOG Genomics Taskforce, the RCOG representative of the Joint Committee on Genomics in Medicine (joint committee of the Royal College of Physicians, Royal College of Pathologists, Royal College of Paediatricians & Child Health, Royal of Obstetricians and Gynaecologists) and a member of the Fetal Group of the British Society of Genetic Medicine. Funding: No external funding provided for this review. Author contributions: JSC and EW researched and wrote the article, contributing equally as joint first authors*. DW, SD and MDK instigated, reviewed and edited the article. SKA reviewed and edited the article. All authors approved the final version.

Cerebral Palsy (CP) describes a heterogenous group of non-progressive disorders of posture or movement, causing activity limitation, due to a lesion in the developing brain. CP is an umbrella term for a heterogenous condition and is, therefore, descriptive rather than a diagnosis. Each case requires detailed consideration of etiology. Our understanding of the underlying cause of CP has developed significantly, with areas such as inflammation, epigenetics and genetic susceptibility to subsequent insults providing new insights. Alongside this, there has been increasing recognition of the multi-organ dysfunction (MOD) associated with CP, in particular in children with higher levels of motor impairment. Therefore, CP should not be seen as an unchanging disorder caused by a solitary insult but rather, as a condition which evolves over time. Assessment of multi-organ function may help to prevent complications in later childhood or adulthood. It may also contribute to an improved understanding of the etiology and thus may have an implication in prevention, interventional methods and therapies. MOD in CP has not yet been quantified and a scoring system may prove useful in allowing advanced clinical planning and follow-up of children with CP. Additionally, several biomarkers hold promise in assisting with long-term monitoring. Clinicians should be aware of the multi-system complications that are associated with CP and which may present significant diagnostic challenges given that many children with CP communicate non-verbally. A step-wise, logical, multi-system approach is required to ensure that the best care is provided to these children. This review summarizes multi-organ dysfunction in children with CP whilst highlighting emerging research and gaps in our knowledge. We identify some potential organ-specific biomarkers which may prove useful in developing guidelines for follow-up and management of these children throughout their lifespan.