Analysis of Whole Genome Sequencing in a Cohort of Individuals with PHACE Syndrome Suggests Dysregulation of RAS/PI3K Signaling

The acronym PHACE stands for the co-occurrence of posterior brain fossa malformations, hemangiomas, arterial anomalies, cardiac defects, and eye abnormalities. The majority of patients have a segmental hemangioma and at least one developmental structural anomaly. The etiology and pathogenesis are unknown. Here we discuss the candidate causative genes identified in a de novo analysis of whole genome sequencing of germline samples from 98 unrelated trios in which the probands had PHACE, all sequenced as part of the Gabriella Miller Kids First Pediatric Research Program. A g:Profiler pathway analysis of the genes with rare, de novo variants suggested dysregulation of the RAS/MAPK and PI3K/AKT pathways that regulate cell growth, migration, and angiogenesis. These findings, along with the developmental anomalies and the vascular birthmark, support including PHACE within the RASopathy family of syndromes.

EPID-14. GABRIELLA MILLER KIDS FIRST DATA RESOURCE CENTER: COLLABORATIVE PLATFORMS FOR ACCELERATING RESEARCH IN PEDIATRIC CANCERS & STRUCTURAL BIRTH DEFECTS

Since launching to the public in September 2018, the Gabriella Miller Kids First Data Resource Center (DRC) has made an increasing number of pediatric genomic studies available to the research community. Currently, 1.3 PBs of genomic and clinical data drawn from 12,000 participants are available across a variety of pediatric cancer and structural birth defect studies. The DRC has architected a secure, cloud-based platform with over 1,300 users that supports the ability of researchers to not only find, access, and reuse data, but also integrate, collaborate, and analyze data quickly at scale. Users can use integrations with platforms such as Cavatica for bioinformatics workflows and PedcBioPortal for cancer genomic visualizations. Additionally, a set of framework services, powered by Gen3, provide a foundation for interoperability with other large-scale data sources, platforms, and a growing ecosystem of analysis and visualization applications. These integrations allow users to search across both TARGET and Kids First clinical data in one location while allowing data governance to be maintained by the original approvers. The new “explore data” feature allows users to search across all studies in order to identify virtual cohorts. Within the portal, these cohorts can be saved and shared with collaborators for iterative refinement and analysis. With appropriate approvals, the associated genomic data can be accessed and analyzed seamlessly in Cavatica or other platforms with interoperable framework services. Additionally, gene searching capabilities will be available in 2020. Data is free to download and cloud credits are available for analysis support.

DEVELOPMENT OF ALGORITHMIC THINKING IN PRESCHOOL AND PRIMARY SCHOOL STUDENTS AT PROGRAMMING AND ROBOTICS CLASSES

The article considers the features of the continuous development of algorithmic thinking in preschoolers and primary school students at programming and robotics classes. The expediency of using various software and hardware tools for preschoolers and primary school students, such as Gigo Kids First Coding & Robotics, the freeware PictoMir, the LEGO Education WeDo robotic kit, and the object-oriented visual programming environment Scratch, is described. Practical tips for using these products are provided.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent–offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case–parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

Orofacial clefts (OFCs) are one of the most common birth defects worldwide and create a significant health burden. The majority of OFCs are non-syndromic, and the genetic component has been only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. Part of the Gabriella Miller Kids First Pediatric Research Program, this is the first large-scale WGS study of OFC in parent-offspring trios. WGS provides deeper and more specific genetic data than currently available using imputation on single nucleotide polymorphic (SNP) marker panels. Here, association analysis of genome-wide single nucleotide variants (SNV) and short insertions and deletions (indels) identified a new locus on chromosome 21 in Colombian families, within a region known to be expressed during craniofacial development. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and the need for larger samples when for studying OFCs and other birth defects in admixed populations.