Pulmonary arterial medial smooth muscle thickness in sudden infant death syndrome: an analysis of subsets of 73 cases

Previous studies addressing pulmonary artery morphology have compared cases of sudden infant death syndrome (SIDS) to controls but none have compared demographic profiles, exposure to potentially hypoxic risk factors and other pathologic variables in SIDS cases grouped according to pulmonary artery medial smooth muscle thickness. Aims: To compare the relative medial thickness (RMT) in alveolar wall arteries (AW) in SIDS cases with that in age-matched controls and 2. Compare demographic, clinical, and pathologic characteristics among three subsets of SIDS cases based upon alveolar wall (AW) RMT. Retrospective morphometric planimetry of all muscularized arteries in standardized right apical lung sections in 73 SIDS cases divided into three groups based on increasing AW RMT as well as 19 controls age-matched to 19 of the SIDS cases. SIDS and age-matched control cases did not differ with respect to AW RMT or other demographic variables. The SIDS group with the thickest AW RMT had significantly more males and premature birth than the other groups, but the groups did not differ for known clinical risk factors that would potentially expose them to hypoxia. Pathologic variables, including pulmonary inflammation, gastric aspiration, intra-alveolar siderophages, cardiac valve circumferences, and heart and liver weights, were not different between groups. Age was not significantly correlated with RMT of alveolar wall and pre-acinar arteries but was significant at p = .018 for small intra-acinar arteries. The groups were different for RMT of small pre-acinar and intra-acinar arteries, which increased with increasing AW RMT. Statistical differences should not necessarily be equated with clinical importance, however future research incorporating more quantified historical data is recommended

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Diffuse Lung Disease in Young Children: Application of a Novel Classification Scheme

Rationale: Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children

Small noncoding differentially methylated copy-number variants, including IncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (IncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including IncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific IncRNAgenes. These deletions define a distant cis-regulatory region that harbors, besides lncRNAgenes, also a differentially methylated CpGisland, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. Wesuggest that lung-transcribed 16q24.1 IncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of IncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development

The formation of the advisory group on risk evaluation education for dementia

BackgroundWhen and how to communicate effectively the results of genetic and biomarker based prediction, detection, and quantification of the brain substrates of dementia involve important ethical and legal issues critical for precision medicine. The urgency of the issue has increased as People Living with Dementia (PLwD) and with Risk for Dementia (PwRD) can access direct to consumer genetic testing, amyloid targeting drugs, and clinical amyloid PET scans. To address the need for effective dissemination and consultation, an advisory group was convened that welcomes all interested members.MethodMembers attend two meetings monthly via phone/computer/WebEx. One meeting is a targeted working group that focuses on the following: 1. Symptomatic (PLwD), 2. Asymptomatic (PwRD), 3. Research, 4. Ethics/Healthcare Law, 5. Trainee/Mentorship. These discussion groups hear from and present to stakeholders (PLwD/PwRD/caregivers, professional organizations, companies) to solicit feedback on the efficacy of their efforts. Members also attend a monthly - all hands- meeting where they receive updates from other groups and hear presentations on emerging research and resources.ResultThe advisory group is composed of 104 members who represent advocacy/stakeholders (21%, e.g. professional organization representatives, (PLwD/PwRD/caregivers, FDA), academia (78%, e.g. university, funders, foundations), and healthcare law (1%). Professions include geneticists, genetic counsellors, researchers, clinicians, ethicists, and lawyers. Motivations for joining include improving communication in research and clinical contexts, mitigating potential negative impacts (e.g.emotional distress or discrimination), and protecting rights to know. Topics have included DTC genomics, the impact of APOE disclosure, genetics and personalized medicine, ecological momentary assessment of response to disclosure, and ethical issues in national and international research registries (EPAD). Activities included a survey on disclosure practices in NIA funded ADCs and collaborations with ADEAR. Stakeholders varied in concerns ranging from a need to protect patients from disclosure to a need to protect the right of access.ConclusionMembership is increasing and is engaging diverse specialties and stakeholders who provide education and consultation around communication and use of genetic and biomarkers related to dementia. The group structure and inclusion of members from multiple organizations supports open and free collaboration. Future efforts will be developing structured education for stakeholders and publications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163965/1/alz045562.pd