@article {955, title = {De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 08}, pages = {e002836}, abstract = {

BACKGROUND: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.

METHODS: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).

RESULTS: Two hundred ninety-four patients (11.7\%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (=5.63{\texttimes}10). In 1268 patients (50.4\%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; =5.33{\texttimes}10) and longer times to final extubation (hazard ratio, 0.74; =0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; =0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; =1.61{\texttimes}10) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.

CONCLUSIONS: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002836}, author = {Boskovski, Marko T and Homsy, Jason and Nathan, Meena and Sleeper, Lynn A and Morton, Sarah and Manheimer, Kathryn B and Tai, Angela and Gorham, Joshua and Lewis, Matthew and Swartz, Michael and Alfieris, George M and Bacha, Emile A and Karimi, Mohsen and Meyer, David and Nguyen, Khanh and Bernstein, Daniel and Romano-Adesman, Angela and Porter, George A and Goldmuntz, Elizabeth and Chung, Wendy K and Srivastava, Deepak and Kaltman, Jonathan R and Tristani-Firouzi, Martin and Lifton, Richard and Roberts, Amy E and Gaynor, J William and Gelb, Bruce D and Kim, Richard and Seidman, Jonathan G and Brueckner, Martina and Mayer, John E and Newburger, Jane W and Seidman, Christine E} } @article {51, title = {Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1249-1255}, abstract = {

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Brain Diseases, Electrophysiology, Epilepsy, Female, Humans, Hyperkinesis, Infant, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree, Synaptic Transmission}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.008}, author = {Madeo, Marianna and Stewart, Michelle and Sun, Yuyang and Sahir, Nadia and Wiethoff, Sarah and Chandrasekar, Indra and Yarrow, Anna and Rosenfeld, Jill A and Yang, Yaping and Cordeiro, Dawn and McCormick, Elizabeth M and Muraresku, Colleen C and Jepperson, Tyler N and McBeth, Lauren J and Seidahmed, Mohammed Zain and El Khashab, Heba Y and Hamad, Muddathir and Azzedine, Hamid and Clark, Karl and Corrochano, Silvia and Wells, Sara and Elting, Mariet W and Weiss, Marjan M and Burn, Sabrina and Myers, Angela and Landsverk, Megan and Crotwell, Patricia L and Waisfisz, Quinten and Wolf, Nicole I and Nolan, Patrick M and Padilla-Lopez, Sergio and Houlden, Henry and Lifton, Richard and Mane, Shrikant and Singh, Brij B and Falk, Marni J and Mercimek-Mahmutoglu, Saadet and Bilguvar, Kaya and Salih, Mustafa A and Acevedo-Arozena, Abraham and Kruer, Michael C} } @article {640, title = {Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Jun 05}, pages = {1011-9}, abstract = {

BACKGROUND AND OBJECTIVES: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.

RESULTS: Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.

CONCLUSIONS: This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

}, keywords = {Adolescent, Atypical Hemolytic Uremic Syndrome, Base Sequence, Blotting, Western, Child, Diacylglycerol Kinase, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Infant, Introns, Male, Molecular Sequence Data, Mutation, Phenotype, Predictive Value of Tests, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.08520814}, author = {Mele, Caterina and Lemaire, Mathieu and Iatropoulos, Paraskevas and Piras, Rossella and Bresin, Elena and Bettoni, Serena and Bick, David and Helbling, Daniel and Veith, Regan and Valoti, Elisabetta and Donadelli, Roberta and Murer, Luisa and Neunh{\"a}userer, Maria and Breno, Matteo and Fremeaux-Bacchi, Veronique and Lifton, Richard and Remuzzi, Giuseppe and Noris, Marina} } @article {225, title = {Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.}, journal = {Circ Res}, volume = {115}, year = {2014}, month = {2014 Oct 24}, pages = {884-896}, abstract = {

RATIONALE: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.

OBJECTIVE: To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.

METHODS AND RESULTS: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7{\texttimes}10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6{\texttimes}10(-4); odds ratio, 3.5) and remained after removing 16\% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.

CONCLUSIONS: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.

}, keywords = {Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Exome, Gene Frequency, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide}, issn = {1524-4571}, doi = {10.1161/CIRCRESAHA.115.304458}, author = {Glessner, Joseph T and Bick, Alexander G and Ito, Kaoru and Homsy, Jason and Rodriguez-Murillo, Laura and Fromer, Menachem and Mazaika, Erica and Vardarajan, Badri and Italia, Michael and Leipzig, Jeremy and DePalma, Steven R and Golhar, Ryan and Sanders, Stephan J and Yamrom, Boris and Ronemus, Michael and Iossifov, Ivan and Willsey, A Jeremy and State, Matthew W and Kaltman, Jonathan R and White, Peter S and Shen, Yufeng and Warburton, Dorothy and Brueckner, Martina and Seidman, Christine and Goldmuntz, Elizabeth and Gelb, Bruce D and Lifton, Richard and Seidman, Jonathan and Hakonarson, Hakon and Chung, Wendy K} }