Person: Agrawal, Pankaj
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Agrawal
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Pankaj
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Agrawal, Pankaj
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Publication De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome(Elsevier, 2018) Torres, Alcy; Brownstein, Catherine; Tembulkar, Sahil K.; Graber, Kelsey; Genetti, Casie; Kleiman, Robin J.; Sweadner, Kathleen; Mavros, Chrystal; Liu, Kevin X.; Smedemark-Margulies, Niklas; Maski, Kiran; Yang, Edward; Agrawal, Pankaj; Shi, Jiahai; Beggs, Alan; D'Angelo, Eugene; Lincoln, Sarah Hope; Carroll, Devon; Dedeoglu, Fatma; Gahl, William A.; Biggs, Catherine M.; Swoboda, Kathryn; Berry, Gerard; Gonzalez-Heydrich, JosephComplex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.Publication Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU(Springer Berlin Heidelberg, 2017) Depienne, Christel; Nava, Caroline; Keren, Boris; Heide, Solveig; Rastetter, Agnès; Passemard, Sandrine; Chantot-Bastaraud, Sandra; Moutard, Marie-Laure; Agrawal, Pankaj; VanNoy, Grace; Stoler, Joan; Amor, David J.; Billette de Villemeur, Thierry; Doummar, Diane; Alby, Caroline; Cormier-Daire, Valérie; Garel, Catherine; Marzin, Pauline; Scheidecker, Sophie; de Saint-Martin, Anne; Hirsch, Edouard; Korff, Christian; Bottani, Armand; Faivre, Laurence; Verloes, Alain; Orzechowski, Christine; Burglen, Lydie; Leheup, Bruno; Roume, Joelle; Andrieux, Joris; Sheth, Frenny; Datar, Chaitanya; Parker, Michael J.; Pasquier, Laurent; Odent, Sylvie; Naudion, Sophie; Delrue, Marie-Ange; Le Caignec, Cédric; Vincent, Marie; Isidor, Bertrand; Renaldo, Florence; Stewart, Fiona; Toutain, Annick; Koehler, Udo; Häckl, Birgit; von Stülpnagel, Celina; Kluger, Gerhard; Møller, Rikke S.; Pal, Deb; Jonson, Tord; Soller, Maria; Verbeek, Nienke E.; van Haelst, Mieke M.; de Kovel, Carolien; Koeleman, Bobby; Monroe, Glen; van Haaften, Gijs; Attié-Bitach, Tania; Boutaud, Lucile; Héron, Delphine; Mignot, CyrilSubtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1772-0) contains supplementary material, which is available to authorized users.Publication Exome sequencing results in successful diagnosis and treatment of a severe congenital anemia(Cold Spring Harbor Laboratory Press, 2016) Lacy, Jessica N.; Ulirsch, Jacob C.; Grace, Rachael; Towne, Meghan C.; Hale, John; Mohandas, Narla; Lux, Samuel; Agrawal, Pankaj; Sankaran, VijayWhole-exome sequencing is increasingly used for diagnosis and identification of appropriate therapies in patients. Here, we present the case of a 3-yr-old male with a lifelong and severe transfusion-dependent anemia of unclear etiology, despite an extensive clinical workup. Given the difficulty of making the diagnosis and the potential side effects from performing interventions in patients with a congenital anemia of unknown etiology, we opted to perform whole-exome sequencing on the patient and his parents. This resulted in the identification of homozygous loss-of-function mutations in the EPB41 gene, encoding erythrocyte protein band 4.1, which therefore causes a rare and severe form of hereditary elliptocytosis in the patient. Based on prior clinical experience in similar patients, a surgical splenectomy was performed that resulted in subsequent transfusion independence in the patient. This case illustrates how whole-exome sequencing can lead to accurate diagnoses (and exclusion of diagnoses where interventions, such as splenectomy, would be contraindicated), thereby resulting in appropriate and successful therapeutic intervention—a major goal of precision medicine.Publication Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease(Cold Spring Harbor Laboratory Press, 2016) Joshi, Mugdha; Anselm, Irina; Shi, Jiahai; Bale, Tejus A.; Towne, Meghan; Schmitz-Abe, Klaus; Crowley, Laura; Giani, Felix C.; Kazerounian, Shideh; Markianos, Kyriacos; Lidov, Hart; Folkerth, Rebecca D.; Sankaran, Vijay; Agrawal, PankajWe describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.Publication AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant(Cold Spring Harbor Laboratory Press, 2017) Morton, Sarah; Prabhu, Sanjay; Lidov, Hart; Shi, Jiahai; Anselm, Irina; Brownstein, Catherine; Bainbridge, Matthew N.; Beggs, Alan; Vargas, Sara; Agrawal, PankajApoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function.Publication A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia(Cold Spring Harbor Laboratory Press, 2016) Smedemark-Margulies, Niklas; Brownstein, Catherine; Vargas, Sigella; Tembulkar, Sahil K.; Towne, Meghan C.; Shi, Jiahai; Gonzalez-Cuevas, Elisa; Liu, Kevin X.; Bilguvar, Kaya; Kleiman, Robin J.; Han, Min-Joon; Torres, Alcy; Berry, Gerard T.; Yu, Timothy W.; Beggs, Alan; Agrawal, Pankaj; Gonzalez-Heydrich, JosephWe describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium–potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.Publication Skeletal Muscle MicroRNA and Messenger RNA Profiling in Cofilin-2 Deficient Mice Reveals Cell Cycle Dysregulation Hindering Muscle Regeneration(Public Library of Science, 2015) Morton, Sarah; Joshi, Mugdha; Savic, Talia; Beggs, Alan; Agrawal, PankajCongenital myopathies are rare skeletal muscle diseases presenting in early age with hypotonia and weakness often linked to a genetic defect. Mutations in the gene for cofilin-2 (CFL2) have been identified in several families as a cause of congenital myopathy with nemaline bodies and cores. Here we explore the global messenger and microRNA expression patterns in quadriceps muscle samples from cofillin-2-null mice and compare them with sibling-matched wild-type mice to determine the molecular pathways and mechanisms involved. Cell cycle processes are markedly dysregulated, with altered expression of genes involved in mitotic spindle formation, and evidence of loss of cell cycle checkpoint regulation. Importantly, alterations in cell cycle, apoptosis and proliferation pathways are present in both mRNA and miRNA expression patterns. Specifically, p21 transcript levels were increased, and the expression of p21 targets, such as cyclin D and cyclin E, was decreased. We therefore hypothesize that deficiency of cofilin-2 is associated with interruption of the cell cycle at several checkpoints, hindering muscle regeneration. Identification of these pathways is an important step towards developing appropriate therapies against various congenital myopathies.Publication The Epithelial Sodium Channel Is a Modifier of the Long-Term Nonprogressive Phenotype Associated with F508del CFTR Mutations(American Thoracic Society, 2017-12) Agrawal, Pankaj; Wang, Ruobing; Li, Hongmei Lisa; Schmitz Abe, Klaus; Simone-Roach, Chantelle; Chen, Jingxin; Shi, Jiahai; Louie, Tin; Sheng, Shaohu; Towne, Meghan C.; Brainson, Christine F.; Matthay, Michael A.; Kim, Carla; Bamshad, Michael; Emond, Mary J.; Gerard, Norma; Kleyman, Thomas R.; Gerard, Craig; Kleyman, ThomasCystic fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability in clinical phenotypes and survival times, even among patients harboring the same genotype. We identified five patients with CF and a homozygous F508del mutation in the CFTR gene who were in their fifth or sixth decade of life and had shown minimal changes in lung function over a longitudinal period of more than 20 years. Because of the rarity of this long-term nonprogressive phenotype, we hypothesized these individuals may carry rare genetic variants in modifier genes that ameliorate disease severity. Individuals at the extremes of survival time and lung-function trajectory underwent whole-exome sequencing, and the sequencing data were filtered to include rare missense, stopgain, indel, and splicing variants present with a mean allele frequency of ,0.2% in general population databases. Epithelial sodium channel (ENaC) mutants were generated via site-directed mutagenesis and expressed for Xenopus oocyte assays. Four of the five individuals carried extremely rare or never reported variants in the SCNN1D and SCNN1B genes of the ENaC. Separately, an independently enriched rare variant in SCNN1D was identified in the Exome Variant Server database associated with a milder pulmonary disease phenotype. Functional analysis using Xenopus oocytes revealed that two of the three variants in d-ENaC encoded by SCNN1D exhibited hypomorphic channel activity. Our data suggest a potential role for d-ENaC in controlling sodium reabsorption in the airways, and advance the plausibility of ENaC as a therapeutic target in CF.