Nel positively regulates the genesis of retinal ganglion cells by promoting their differentiation and survival during development

Peer reviewedPublisher PD

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome

Precision Newborn Screening for Lysosomal Disorders

Purpose: The implementation of newborn screening for lysosomal disorders has uncovered overall poor specificity, psychosocial harm experienced by caregivers, and costly follow-up testing of false-positive cases. We report an informatics solution proven to minimize these issues. Methods: The Kentucky Department for Public Health outsourced testing for mucopolysaccharidosis type I (MPS I) and Pompe disease, conditions recently added to the recommended uniform screening panel, plus Krabbe disease, which was added by legislative mandate. A total of 55,161 specimens were collected from infants born over 1 year starting from February 2016. Testing by tandem mass spectrometry was integrated with multivariate pattern recognition software (Collaborative Laboratory Integrated Reports), which is freely available to newborn screening programs for selection of cases for which a biochemical second-tier test is needed. Results: Of five presumptive positive cases, one was affected with infantile Krabbe disease, two with Pompe disease, and one with MPS I. The remaining case was a heterozygote for the latter condition. The false-positive rate was 0.0018% and the positive predictive value was 80%. Conclusion: Postanalytical interpretive tools can drastically reduce false-positive outcomes, with preliminary evidence of no greater risk of false-negative events, still to be verified by long-term surveillance

Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child–parent trios, one child–mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case–control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex

Discriminatory ability of calcaneal quantitative ultrasound in the assessment of bone status in patients with inflammatory bowel disease

A high incidence of bone disease in patients with inflammatory bowel disease (IBD) requires frequent monitoring of skeletal status and, for that reason, evaluation of radiation-free technology is an issue of interest. Our objective was to appraise the parameters of calcaneal quantitative ultrasound (QUS): broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI), and establish their t-score values to investigate discriminatory ability of QUS in IBD patients with metabolic bone disease. The study included 126 patients (Crohn's disease [n = 94] and ulcerative colitis [n = 32]), and 228 age- and sex-matched healthy volunteers. Bone status was evaluated on the same day by calcaneal QUS and dual-energy x-ray absorptiometry (DXA) at spine (L1-L4) and total hip. All QUS measurements were lower in patients compared with healthy controls (BUA p < 0.001; SOS p < 0.001; QUI p < 0.001) and correlated significantly but inversely with disease duration (r = -0.3, p = 0.002). There was no difference with respect to type of disease (Crohn's disease or ulcerative colitis) or corticosteroid therapy. All three QUS t-scores were significantly lower in patients who had previously sustained fragile fractures (n = 28) than in those without fracture in their history (n = 98) (t-scores: BUA -2.0 vs. -1.3, p = 0.008; SOS -2.1 vs. -1.4, p = 0.02: QUI -2.3 vs. -1.5, p = 0.009). Axial DXA was not significantly different between the fracture and nonfracture patients (-1.7 vs. -1.2, p = 0.1), whereas total hip DXA showed a discriminatory power between the two (-1.6 vs. -0.7, p = 0.001). Patients with t-score < -1.0 scanned by DXA were classified as bone disease. The sensitivity of QUS to identify bone disease was 93% and specificity 63%. The sensitivity of QUS to detect osteopenia was 84% and 72% for osteoporosis. Alternatively, lower negative QUS t-score cutoff </= -1.8 identified 83% of osteoporosis at lumbar spine and 100% at total hip. All three QUS variables had t-scores less than -1.8 when osteoporosis was detected at both spine and hip. However, the subgroup of IBD patients with QUI t-score cutoff </= -1.8 still included 26% of individuals with normal bone status. Calcaneal QUS measurements may identify patients with IBD who are at a higher risk of fracture independently of DXA measurements. However, QUS showed poor agreement with bone status scanned by DXA and a low discriminatory power between osteopenia and osteoporosis

Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements

Key Points Question What is the diagnostic yield of newborn screening for biliary atresia using direct or conjugated bilirubin measurements? Findings In this study that involved 124 385 newborns, a 2-stage screening approach based on direct or conjugated bilirubin measurements identified the 7 known infants with biliary atresia with a sensitivity of 100.0% and a specificity of 99.9%, although the 95% CI around the sensitivity was wide and the study design did not ensure complete ascertainment of false-negative results. Meaning These findings may help inform decision-making about newborn screening for biliary atresia, although further research is needed from larger populations to obtain more precise estimates of diagnostic yield and to better understand clinical outcomes and cost-effectiveness of this screening approach. Abstract Importance Treating biliary atresia in newborns earlier can delay or prevent the need for liver transplant; however, treatment typically occurs later because biliary atresia is difficult to detect during its early stages. Objective To determine the diagnostic yield of newborn screening for biliary atresia with direct or conjugated bilirubin measurements and to evaluate the association of screening implementation with clinical outcomes. Design, Setting, and Participants A cross-sectional screening study of 124 385 infants born at 14 Texas hospitals between January 2015 and June 2018; and a pre-post study of 43 infants who underwent the Kasai portoenterostomy as treatment for biliary atresia at the region’s largest pediatric hepatology center before (January 2008-June 2011) or after (January 2015-June 2018) screening implementation. Final follow-up occurred on July 15, 2019. Exposures Two-stage screening with direct or conjugated bilirubin measurements. In stage 1, all newborns were tested within the first 60 hours of life, with a positive screening result defined as bilirubin levels exceeding derived 95th percentile reference intervals. In stage 2, infants who had a positive screening result in stage 1 were retested at or before the 2-week well-child visit, with a positive screening result defined as bilirubin levels greater than the stage 1 result or greater than 1 mg/dL. Main Outcomes and Measures The primary outcomes of the screening study were sensitivity, specificity, positive predictive value, and negative predictive value based on infants testing positive in both stages. The reference standard was biliary atresia diagnosed at the region’s pediatric hepatology centers. The primary outcome of the pre-post study was the age infants underwent the Kasai portoenterostomy for treatment of biliary atresia. Results Of 124 385 newborns in the screening study, 49.2% were female, 87.6% were of term gestational age, 70.0% were white, and 48.1% were Hispanic. Screening identified the 7 known infants with biliary atresia with a sensitivity of 100% (95% CI, 56.1%-100.0%), a specificity of 99.9% (95% CI, 99.9%-99.9%), a positive predictive value of 5.9% (95% CI, 2.6%-12.2%), and a negative predictive value of 100.0% (95% CI, 100.0%-100.0%). In the pre-post study, 24 infants were treated before screening implementation and 19 infants were treated after screening implementation (including 6 of 7 from the screening study, 7 from screening at nonstudy hospitals, and 6 from referrals because of clinical symptoms). The age infants underwent the Kasai portoenterostomy was significantly younger after screening was implemented (mean age, 56 days [SD, 19 days] before screening implementation vs 36 days [SD, 22 days] after screening implementation; between-group difference, 19 days [95% CI, 7-32 days]; P = .004). Conclusions and Relevance Newborn screening with direct or conjugated bilirubin measurements detected all known infants with biliary atresia in the study population, although the 95% CI around the sensitivity estimate was wide and the study design did not ensure complete ascertainment of false-negative results. Research is needed in larger populations to obtain more precise estimates of diagnostic yield and to better understand the clinical outcomes and cost-effectiveness of this screening approach