Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation
Sci Transl Med. 2019 Apr 24;11(489):eaat6177. doi: 10.1126/scitranslmed.aat6177. ABSTRACT By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform […]
Effect of Sociodemographic Factors on Uptake of a Patient-Facing Information Technology Family Health History Risk Assessment Platform
Appl Clin Inform. 2019 Mar;10(2):180-188. doi: 10.1055/s-0039-1679926. Epub 2019 Mar 13. ABSTRACT OBJECTIVE: Investigate sociodemographic differences in the use of a patient-facing family health history (FHH)-based risk assessment platform. METHODS: In this large multisite trial with a diverse patient population, we evaluated the relationship between sociodemographic factors and FHH health risk assessment uptake using an […]
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
Nat Commun. 2019 Feb 12;10(1):707. doi: 10.1038/s41467-018-07067-3. ABSTRACT Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report […]
Blacklisting variants common in private cohorts but not in public databases optimizes human exome analysis
Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):950-959. doi: 10.1073/pnas.1808403116. Epub 2018 Dec 27. ABSTRACT Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient’s exome with public databases to remove reported variants inconsistent […]
Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria
Genet Med. 2019 Aug;21(8):1851-1867. doi: 10.1038/s41436-018-0403-z. Epub 2018 Dec 14. ABSTRACT PURPOSE: Phenylketonuria (PKU) is a rare metabolic disorder that requires life-long management to reduce phenylalanine (Phe) concentrations within the recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can metabolize Phe) as a new therapy necessitates the provision of guidance for its use. […]
MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)
J Med Genet. 2019 May;56(5):332-339. doi: 10.1136/jmedgenet-2018-105623. Epub 2018 Nov 28. ABSTRACT BACKGROUND: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including […]
Elucidating the molecular pathogenesis of glioma: integrated germline and somatic profiling of a familial glioma case series.
Neuro Oncol. 2018 Nov 12;20(12):1625-1633. doi: 10.1093/neuonc/noy119. PMID: 30165405; PMCID: PMC6231201. Abstract Key points: 1. Familial and sporadic gliomas display highly comparable molecular landscapes. 2. Germline and somatic molecular events target common core pathways involved in gliomagenesis. 3. Carriage of germline glioma risk variants is not associated with somatic events in the same gene. PMID: 30165405 | […]
A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome
Cell Rep. 2018 Nov 6;25(6):1469-1484.e5. doi: 10.1016/j.celrep.2018.10.036. ABSTRACT Patients with mtDNA depletion syndrome 3 (MTDPS3) often die as children from liver failure caused by severe reduction in mtDNA content. The identification of treatments has been impeded by an inability to culture and manipulate MTDPS3 primary hepatocytes. Here we generated DGUOK-deficient hepatocyte-like cells using induced pluripotent […]
Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease
Genet Med. 2019 May;21(5):1121-1130. doi: 10.1038/s41436-018-0295-y. Epub 2018 Oct 8. ABSTRACT PURPOSE: Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically […]
Heterozygous WNT1 variant causing a variable bone phenotype
Am J Med Genet A. 2018 Nov;176(11):2419-2424. doi: 10.1002/ajmg.a.40347. Epub 2018 Sep 24. ABSTRACT Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in WNT1 cause […]