VarFish - Collaborative and comprehensive variant analysis for diagnosis and research

VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of panel and exome variant data for rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Filtered variants are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows user to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software’s extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g., after update of genotype or phenotype databases

Human genetics education for middle and secondary science teachers. Third annual report, April 1, 1994--March 30, 1995

This project is designed to increase teachers` knowledge of the Human Genome Project (HGP) with a focus on the ethical, legal and social implications of genetic technology. The project provides educators with the newest information on human genetics including applications of genetic technology, updated teaching resources and lesson plans, peer teaching ideas to disseminate genetic information to students and other educators, and established liaisons with genetic professionals

De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunction

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.N.E. is a participant in the Berlin Institute of Health Charité Clinician Scientist Program, funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health. S.M. was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) and the Max Planck Foundation, B.W. was supported by grants from the DFG SFB1002 project D02, and B.F.-Z. was supported by a grant from the DFG (FI 2240/1-1). U.K. received funding from FP7-EU grant agreement no. 602300 (SYBIL) and the DFG Research Unit FOR 2165 (249509554). Research reported in this publication was supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS08372 to P.E.B

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal Factin polymerization and dysregulated protein recycling.Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies, feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers