Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma
Sci Signal. 2018 Sep 11;11(547):eaau5147. doi: 10.1126/scisignal.aau5147. ABSTRACT A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and […]
Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)
Hum Genet. 2018 Sep;137(9):753-768. doi: 10.1007/s00439-018-1929-5. Epub 2018 Aug 23. ABSTRACT NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal […]
De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy
Genet Med. 2019 Apr;21(4):1008-1014. doi: 10.1038/s41436-018-0143-0. Epub 2018 Aug 31. ABSTRACT PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy […]
Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes
Ann Clin Transl Neurol. 2018 Jul 17;5(8):996-1010. doi: 10.1002/acn3.597. eCollection 2018 Aug. ABSTRACT Paroxysmal movement disorders encompass varied motor phenomena. Less recognized features and wide phenotypic and genotypic heterogeneity are impediments to straightforward molecular diagnosis. We describe a family with episodic ataxia type 1, initially mis-characterized as paroxysmal dystonia to illustrate this diagnostic challenge. We […]
Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures
Cell. 2018 Sep 6;174(6):1559-1570.e22. doi: 10.1016/j.cell.2018.07.019. Epub 2018 Aug 9. ABSTRACT The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed “UC dysregulation” (UCD). UCD elicits nitrogen […]
Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
Am J Hum Genet. 2018 Sep 6;103(3):431-439. doi: 10.1016/j.ajhg.2018.07.010. Epub 2018 Aug 9. ABSTRACT ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of […]
Genomic sequencing in acutely ill infants: what will it take to demonstrate clinical value?
Genet Med. 2019 Feb;21(2):269-271. doi: 10.1038/s41436-018-0124-3. Epub 2018 Aug 13. NO ABSTRACT PMID:30100610 | PMC:PMC6691721 | DOI:10.1038/s41436-018-0124-3
Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome
Am J Hum Genet. 2018 Aug 2;103(2):296-304. doi: 10.1016/j.ajhg.2018.06.011. Epub 2018 Jul 19. ABSTRACT The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous […]
Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration
Nat Genet. 2018 Aug;50(8):1093-1101. doi: 10.1038/s41588-018-0166-0. Epub 2018 Jul 16. ABSTRACT Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss […]
Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases
NPJ Genom Med. 2018 Jul 9;3:16. doi: 10.1038/s41525-018-0053-8. eCollection 2018. ABSTRACT Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes […]