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To determine detection rates of genetic disease in a level IV neonatal intensive care unit (NICU) and cost of care.We divided 2703 neonates, admitted between 2013 and 2016 to a level IV NICU, into two epochs and determined how genetic testing utilization, genetic diagnoses identified, and cost of NICU care changed over time.The increasing use of multi-gene panels 104 vs 184 (P = 0.02) and whole exome sequencing (WES) 9 vs 28 (P = 0.03) improved detection of genetic disease, 9% vs 12% (P 0.01). Individuals with genetic diagnoses had higher mean NICU charges, $723,422 vs $417,013 (P 0.01) secondary to longer lengths of stay, not genetic services.The increased utilization of broad genetic testing improved the detection of genetic disease but contributed minimally to the cost of care while bolstering understanding of the patient's condition and prognosis.

A female infant is born at 35 weeks, 4 days of gestation to a 29-year-old gravida 1, para 1 mother via cesarean section because of a footling breech presentation. The mother had received adequate prenatal care and had normal ultrasonography scans except for the finding of a 2-vessel cord and an infant who was small for gestational age. Maternal infectious laboratory findings are negative. Delivery is uneventful and Apgar scores at 1 minute and 5 minutes are 7 and 9, respectively. The infant’s birthweight is 1,920 g (0.35%, Z −2.69), birth length is 44.5 cm (1.46%, Z −2.18), and head circumference is 29.8 cm. (0.02%, Z −3.6) Around 85 minutes after birth, because of jitteriness, the infant’s blood glucose (BG) is measured and found to be 21 mg/dL (1.17 mmol/L). She is offered preterm infant formula 22 kcal/oz, of which, she took around 10 mL, and repeat BG is found to be 27 mg/dL (1.5 mmol/L). A peripheral intravenous catheter is placed and a 2 mL/kg bolus of 10% dextrose (D10) given, and an infusion of D10 in water at the rate of 80 mL/kg per day is started. Repeat BG is 88 mg/dL (4.9 mmol/L). On day 2 after birth, she starts having choking episodes and nonbilious emesis with feeding. Abdominal radiography shows a nonobstructive bowel gas pattern. She is transferred to the NICU and a nasogastric (NG) tube placed for feeding. Her BG levels remain stable with NG feedings, and she continues to be in room air with no evidence of respiratory distress. A sepsis evaluation is completed, with rule-out antibiotics (ampicillin and gentamycin) for 48 hours, with negative findings noted on culture. Echocardiography and head ultrasonography findings are normal, renal ultrasonography shows normal kidneys and a questionable bicornuate uterus. Physical examination findings are otherwise normal except for …

More and more women rely on non-invasive prenatal screening (NIPS) to detect fetal sex and risk for aneuploidy. The testing applies massively parallel sequencing or single nucleotide polymorphism (SNP) microarray to circulating cell-free DNA to determine relative copy number. In addition to trisomies 13, 18, and 21, some labs offer screening for sex chromosome abnormalities as part of their test. In this study, an index neonate screened positive for monosomy X and had discordant postnatal chromosomes indicating an X;autosome translocation. This patient prompted a retrospective chart review for similar cases at a large NIPS testing center. The review found 28 patients with an abnormal NIPS for monosomy X who were eventually diagnosed with additional discrepant structural sex chromosome abnormalities including translocations, isochromosomes, deletions, rings, markers, and uniparental disomy. The majority of these were mosaic with monosomy X, but in seven cases, there was no evidence of mosaicism on confirmatory testing. The identification of multiple sex chromosome aneuploidies in these cases supports the need for additional genetic counseling prior to NIPS testing and following abnormal NIPS results that are positive for monosomy X. This finding broadens our knowledge about the variable outcomes of positive monosomy X NIPS results and emphasizes the importance of confirmatory testing and clinical follow up for these patients.

CHARGE syndrome (OMIM 214800) is a condition characterized by multisystem involvement with CHD7 pathogenic mutations leading to disease in the majority of patients. Discovery of the molecular cause of CHARGE unmasked a larger phenotypic spectrum than was previously appreciated. Within our interdisciplinary CHARGE syndrome program, we sought to characterize our CHD7-positive CHARGE cohort without coloboma or choanal atresia, highlighting complications and outcomes. We describe 18 individuals with CHD7-confirmed diagnosis from 15 families. The most sensitive finding in the cohort was temporal bone malformations, present in 13/15 individuals. Individuals had an average of 1.6 major features and 3.3 minor features defined by the Blake et al. guidelines. Despite lack of major features or major malformations, the majority of individuals continued to have difficulties with pneumonia, aspiration, secretion management and motility issues that greatly impacted their lives. Our findings illustrate the need for molecular testing and timely recognition given that the major co-morbidities are frequently experienced by patients with the mildest clinical spectrum of CHARGE syndrome.

Proteus syndrome (PS) is a rare disorder caused by a mosaic AKT1 variant that comprises patchy overgrowth of tissues derived from all three germinal layers affecting multiple viscera. We sought to delineate the extent of hepatoportal manifestations in patients with PS. We identified patients with PS who had abdominal imaging from 1989 to 2015 in a natural history study. Imaging was characterized for evidence of focal findings in the liver, spleen, and portal vasculature and for organomegaly. Relevant clinical and laboratory data were compared among those with or without organomegaly. Abdominal imaging was available on 38 patients including 20 who had serial studies. Nine patients had focal hepatic lesions including vascular malformations (VMs). Focal splenic abnormalities were noted in seven patients. Patients without cutaneous VMs did not have visceral VMs. Nine patients had splenomegaly, 12 had portal vein dilation, and 4 had hepatomegaly. There was a weak correlation of portal vein dilation to spleen height ratio (r(2) = 0.18, p < .05). On laboratory evaluation, hepatic function was normal but there was thrombocytopenia in those with splenomegaly; platelet counts were 179 ± 87K/μL compared to those with normal spleen size at 253 ± 57K/μL (p < .05). Overall, focal hepatosplenic abnormalities occurred in 11 of 38 (29%) patients with PS. Splenomegaly and portal venous dilation were both found in 8 of 38 (21%) patients; however, other than relative thrombocytopenia, there was no evidence of portal hypertension. Although the AKT1-E17K somatic variant is a suspected oncogene, there were no malignant lesions identified in this study.

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published

To determine whether residential environmental tobacco smoke (ETS) exposure during pregnancy is associated with low birth weight (LBW) neonates and establish a dose response relationship.Case control study.Tertiary care hospital.Mothers giving birth to LBW neonate (2.5 kg) were cases and those whose neonates weighed =2.5 kg at birth were controls. Excluded were women smokers and tobacco chewers, high parity (3), multiple pregnancy and still births. Included were 100 cases and 200 controls, aged 20 to 30 years. Information was collected on ETS exposure and other risk factors of LBW within 24 hours of delivery. Clinical information like maternal haemoglobin levels, birth weight and gestational age of the neonate was extracted from hospital records.On univariate analysis, preterm pregnancy, low socioeconomic status, previous LBW neonate, no utilization of antenatal care (ANC), severe anemia and ETS exposure were statistically significantly associated with LBW neonate and controlling for these in logistic regression analysis, adjusted Odds ratio for ETS exposure association with LBW neonate was 3.16 (95% CI=1.88-5.28). A dose response relationship was also found which was statistically significant (10-20 cigarettes smoked/day: OR = 4.06, 95% CI=1.78-9.26 and20 cigarettes smoked/day, OR = 17.62, 95% CI= 3.76-82.43).Exposure to ETS during pregnancy is associated with LBW of neonates. Hence, there is an urgent need to increase awareness about health hazards of ETS during pregnancy and bring about behavioural changes accordingly as a one of the strategies to reduce LBW deliveries in India.