@article {790, title = {Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 05 01}, pages = {1447-1461}, abstract = {

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

}, keywords = {Abnormalities, Multiple, Epileptic Syndromes, Female, Glutamate Decarboxylase, Humans, Infant, Newborn, Male, Mutation, Pedigree}, issn = {1460-2156}, doi = {10.1093/brain/awaa085}, author = {Chatron, Nicolas and Becker, Felicitas and Morsy, Heba and Schmidts, Miriam and Hardies, Katia and Tuysuz, Beyhan and Roselli, Sandra and Najafi, Maryam and Alkaya, Dilek Uludag and Ashrafzadeh, Farah and Nabil, Amira and Omar, Tarek and Maroofian, Reza and Karimiani, Ehsan Ghayoor and Hussien, Haytham and Kok, Fernando and Ramos, Luiza and Gunes, Nilay and Bilguvar, Kaya and Labalme, Audrey and Alix, Eudeline and Sanlaville, Damien and de Bellescize, Julitta and Poulat, Anne-Lise and Moslemi, Ali-Reza and Lerche, Holger and May, Patrick and Lesca, Gaetan and Weckhuysen, Sarah and Tajsharghi, Homa} } @article {914, title = {Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.}, journal = {Nat Med}, volume = {26}, year = {2020}, month = {2020 11}, pages = {1754-1765}, abstract = {

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17\% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22\% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

}, keywords = {Brain, Cerebral Ventricles, Exome, Female, Genetic Predisposition to Disease, Humans, Hydrocephalus, Male, Mutation, Neural Stem Cells, Neurogenesis, Neuroglia, Transcription Factors, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Whole Exome Sequencing}, issn = {1546-170X}, doi = {10.1038/s41591-020-1090-2}, author = {Jin, Sheng Chih and Dong, Weilai and Kundishora, Adam J and Panchagnula, Shreyas and Moreno-De-Luca, Andres and Furey, Charuta G and Allocco, August A and Walker, Rebecca L and Nelson-Williams, Carol and Smith, Hannah and Dunbar, Ashley and Conine, Sierra and Lu, Qiongshi and Zeng, Xue and Sierant, Michael C and Knight, James R and Sullivan, William and Duy, Phan Q and DeSpenza, Tyrone and Reeves, Benjamin C and Karimy, Jason K and Marlier, Arnaud and Castaldi, Christopher and Tikhonova, Irina R and Li, Boyang and Pe{\~n}a, Helena Perez and Broach, James R and Kabachelor, Edith M and Ssenyonga, Peter and Hehnly, Christine and Ge, Li and Keren, Boris and Timberlake, Andrew T and Goto, June and Mangano, Francesco T and Johnston, James M and Butler, William E and Warf, Benjamin C and Smith, Edward R and Schiff, Steven J and Limbrick, David D and Heuer, Gregory and Jackson, Eric M and Iskandar, Bermans J and Mane, Shrikant and Haider, Shozeb and Guclu, Bulent and Bayri, Yasar and Sahin, Yener and Duncan, Charles C and Apuzzo, Michael L J and DiLuna, Michael L and Hoffman, Ellen J and {\v S}estan, Nenad and Ment, Laura R and Alper, Seth L and Bilguvar, Kaya and Geschwind, Daniel H and G{\"u}nel, Murat and Lifton, Richard P and Kahle, Kristopher T} } @article {917, title = {Human CRY1 variants associate with attention deficit/hyperactivity disorder.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 07 01}, pages = {3885-3900}, abstract = {

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1\% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.

}, keywords = {Adult, ARNTL Transcription Factors, Attention Deficit Disorder with Hyperactivity, CLOCK Proteins, Cryptochromes, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Mutation, Sleep Disorders, Circadian Rhythm}, issn = {1558-8238}, doi = {10.1172/JCI135500}, author = {Onat, O Emre and Kars, M Ece and G{\"u}l, {\c S}eref and Bilguvar, Kaya and Wu, Yiming and {\"O}zhan, Ay{\c s}e and Ayd{\i}n, Cihan and Ba{\c s}ak, A Nazl{\i} and Trusso, M Allegra and Goracci, Arianna and Fallerini, Chiara and Renieri, Alessandra and Casanova, Jean-Laurent and Itan, Yuval and Atba{\c s}o{\u g}lu, Cem E and Saka, Meram C and Kavakl{\i}, {\.I} Halil and Ozcelik, Tayfun} } @article {794, title = {Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {2020 10}, pages = {1046-1056}, abstract = {

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14\% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

}, keywords = {Animals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-020-0695-1}, author = {Jin, Sheng Chih and Lewis, Sara A and Bakhtiari, Somayeh and Zeng, Xue and Sierant, Michael C and Shetty, Sheetal and Nordlie, Sandra M and Elie, Aureliane and Corbett, Mark A and Norton, Bethany Y and van Eyk, Clare L and Haider, Shozeb and Guida, Brandon S and Magee, Helen and Liu, James and Pastore, Stephen and Vincent, John B and Brunstrom-Hernandez, Janice and Papavasileiou, Antigone and Fahey, Michael C and Berry, Jesia G and Harper, Kelly and Zhou, Chongchen and Zhang, Junhui and Li, Boyang and Zhao, Hongyu and Heim, Jennifer and Webber, Dani L and Frank, MAHlia S B and Xia, Lei and Xu, Yiran and Zhu, Dengna and Zhang, Bohao and Sheth, Amar H and Knight, James R and Castaldi, Christopher and Tikhonova, Irina R and L{\'o}pez-Gir{\'a}ldez, Francesc and Keren, Boris and Whalen, Sandra and Buratti, Julien and Doummar, Diane and Cho, Megan and Retterer, Kyle and Millan, Francisca and Wang, Yangong and Waugh, Jeff L and Rodan, Lance and Cohen, Julie S and Fatemi, Ali and Lin, Angela E and Phillips, John P and Feyma, Timothy and MacLennan, Suzanna C and Vaughan, Spencer and Crompton, Kylie E and Reid, Susan M and Reddihough, Dinah S and Shang, Qing and Gao, Chao and Novak, Iona and Badawi, Nadia and Wilson, Yana A and McIntyre, Sarah J and Mane, Shrikant M and Wang, Xiaoyang and Amor, David J and Zarnescu, Daniela C and Lu, Qiongshi and Xing, Qinghe and Zhu, Changlian and Bilguvar, Kaya and Padilla-Lopez, Sergio and Lifton, Richard P and Gecz, Jozef and MacLennan, Alastair H and Kruer, Michael C} } @article {542, title = {Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.}, journal = {Mol Genet Genomic Med}, volume = {6}, year = {2018}, month = {2018 03}, pages = {230-248}, abstract = {

BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage.

METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations.

RESULTS: We found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4~years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20~years old. All patients presented developmental coxa vara and seven patients (~22\%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene.

CONCLUSION: With this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense-mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.

}, keywords = {Adolescent, Adult, Arthropathy, Neurogenic, Child, Child, Preschool, Coxa Vara, Exons, Female, Genetic Association Studies, Hand Deformities, Congenital, Humans, Male, Middle Aged, Mutation, Proteoglycans, Retrospective Studies, Sequence Deletion, Synovitis, Whole Exome Sequencing}, issn = {2324-9269}, doi = {10.1002/mgg3.364}, author = {Yilmaz, Saliha and Uluda{\u g} Alkaya, Dilek and Kasapcopur, Ozgur and Barut, Kenan and Akdemir, Ekin S and Celen, Cemre and Youngblood, Mark W and Yasuno, Katsuhito and Bilguvar, Kaya and G{\"u}nel, Murat and Tuysuz, Beyhan} } @article {351, title = {Biallelic mutations in the 3{\textquoteright} exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {457-464}, abstract = {

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg-dependent 3{\textquoteright}-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3{\textquoteright} genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3{\textquoteright}-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3{\textquoteright}-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3{\textquoteright} ends.

}, keywords = {Alleles, Animals, Cerebellar Diseases, Exonucleases, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Nuclear Proteins, RNA, Messenger, RNA, Small Nuclear, Spliceosomes, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3762}, author = {Lardelli, Rea M and Schaffer, Ashleigh E and Eggens, Veerle R C and Zaki, Maha S and Grainger, Stephanie and Sathe, Shashank and Van Nostrand, Eric L and Schlachetzki, Zinayida and Rosti, Basak and Akizu, Naiara and Scott, Eric and Silhavy, Jennifer L and Heckman, Laura Dean and Rosti, Rasim Ozgur and Dikoglu, Esra and Gregor, Anne and Guemez-Gamboa, Alicia and Musaev, Damir and Mande, Rohit and Widjaja, Ari and Shaw, Tim L and Markmiller, Sebastian and Marin-Valencia, Isaac and Davies, Justin H and de Meirleir, Linda and Kayserili, H{\"u}lya and Altunoglu, Umut and Freckmann, Mary Louise and Warwick, Linda and Chitayat, David and Blaser, Susan and {\c C}a{\u g}layan, Ahmet Okay and Bilguvar, Kaya and Per, H{\"u}seyin and Fagerberg, Christina and Christesen, Henrik T and Kibaek, Maria and Aldinger, Kimberly A and Manchester, David and Matsumoto, Naomichi and Muramatsu, Kazuhiro and Saitsu, Hirotomo and Shiina, Masaaki and Ogata, Kazuhiro and Foulds, Nicola and Dobyns, William B and Chi, Neil C and Traver, David and Spaccini, Luigina and Bova, Stefania Maria and Gabriel, Stacey B and G{\"u}nel, Murat and Valente, Enza Maria and Nassogne, Marie-Cecile and Bennett, Eric J and Yeo, Gene W and Baas, Frank and Lykke-Andersen, Jens and Gleeson, Joseph G} } @article {426, title = {Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Nov}, pages = {1593-1601}, abstract = {

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8\%, including a recessive founder mutation in GDF1 accounting for \~{}5\% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for \~{}11\% of Shone complex, and dominant FLT4 mutations accounting for 2.3\% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8\% of cases, including \~{}3\% of isolated CHD patients and \~{}28\% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70\% probability of being disease related. DNMs in \~{}440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

}, keywords = {Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3}, issn = {1546-1718}, doi = {10.1038/ng.3970}, author = {Jin, Sheng Chih and Homsy, Jason and Zaidi, Samir and Lu, Qiongshi and Morton, Sarah and DePalma, Steven R and Zeng, Xue and Qi, Hongjian and Chang, Weni and Sierant, Michael C and Hung, Wei-Chien and Haider, Shozeb and Zhang, Junhui and Knight, James and Bjornson, Robert D and Castaldi, Christopher and Tikhonoa, Irina R and Bilguvar, Kaya and Mane, Shrikant M and Sanders, Stephan J and Mital, Seema and Russell, Mark W and Gaynor, J William and Deanfield, John and Giardini, Alessandro and Porter, George A and Srivastava, Deepak and Lo, Cecelia W and Shen, Yufeng and Watkins, W Scott and Yandell, Mark and Yost, H Joseph and Tristani-Firouzi, Martin and Newburger, Jane W and Roberts, Amy E and Kim, Richard and Zhao, Hongyu and Kaltman, Jonathan R and Goldmuntz, Elizabeth and Chung, Wendy K and Seidman, Jonathan G and Gelb, Bruce D and Seidman, Christine E and Lifton, Richard P and Brueckner, Martina} } @article {20, title = {ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.}, journal = {Proc Natl Acad Sci U S A}, volume = {113}, year = {2016}, month = {2016 Oct 04}, pages = {11289-11293}, abstract = {

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient{\textquoteright}s liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

}, keywords = {Ataxia, Bile Acids and Salts, Child, Cognitive Dysfunction, Homozygote, Humans, Infant, Infant, Newborn, Liver, Liver Cirrhosis, Loss of Function Mutation, Male, Mutation, Oxidation-Reduction, Oxidoreductases, Transaminases}, issn = {1091-6490}, doi = {10.1073/pnas.1613228113}, author = {Vilarinho, S{\'\i}lvia and Sari, Sinan and Mazzacuva, Francesca and Bilguvar, Kaya and Esendagli-Yilmaz, G{\"u}ldal and Jain, Dhanpat and Akyol, G{\"u}len and Dalgi{\c c}, Buket and G{\"u}nel, Murat and Clayton, Peter T and Lifton, Richard P} } @article {14, title = {Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1181-1189}, abstract = {

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.

}, keywords = {Alleles, Amino Acid Sequence, Basement Membrane, Brain, Carrier Proteins, Cerebellum, Cobblestone Lissencephaly, Developmental Disabilities, Dystroglycans, Eye Abnormalities, Female, Humans, Infant, Male, Membrane Proteins, Mutation, Nervous System Malformations, Neuroglia, Neurons, Pedigree, Phenotype}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.007}, author = {Jerber, Julie and Zaki, Maha S and Al-Aama, Jumana Y and Rosti, Rasim Ozgur and Ben-Omran, Tawfeg and Dikoglu, Esra and Silhavy, Jennifer L and Caglar, Caner and Musaev, Damir and Albrecht, Beate and Campbell, Kevin P and Willer, Tobias and Almuriekhi, Mariam and {\c C}a{\u g}layan, Ahmet Okay and Vajsar, Jiri and Bilguvar, Kaya and Ogur, Gonul and Abou Jamra, Rami and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {410, title = {Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.}, journal = {Cell}, volume = {167}, year = {2016}, month = {2016 Dec 01}, pages = {1481-1494.e18}, abstract = {

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

}, keywords = {Amino Acids, Animals, Autism Spectrum Disorder, Blood-Brain Barrier, Brain, Female, Humans, Infant, Infant, Newborn, Large Neutral Amino Acid-Transporter 1, Male, Mice, Mice, Knockout, Mutation, Pedigree, Protein Biosynthesis, Receptor, TIE-2}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.11.013}, author = {T{\u a}rlungeanu, Dora C and Deliu, Elena and Dotter, Christoph P and Kara, Majdi and Janiesch, Philipp Christoph and Scalise, Mariafrancesca and Galluccio, Michele and Tesulov, Mateja and Morelli, Emanuela and Sonmez, Fatma Mujgan and Bilguvar, Kaya and Ohgaki, Ryuichi and Kanai, Yoshikatsu and Johansen, Anide and Esharif, Seham and Ben-Omran, Tawfeg and Topcu, Meral and Schlessinger, Avner and Indiveri, Cesare and Duncan, Kent E and {\c C}a{\u g}layan, Ahmet Okay and G{\"u}nel, Murat and Gleeson, Joseph G and Novarino, Gaia} } @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 {11, title = {Two locus inheritance of non-syndromic midline craniosynostosis via rare and common alleles.}, journal = {Elife}, volume = {5}, year = {2016}, month = {2016 Sep 08}, abstract = {

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7\%) had damaging de novo or rare transmitted mutations in , an inhibitor of BMP - induced osteoblast differentiation (p<10). mutations nonetheless showed striking incomplete penetrance (<60\%). Genotypes of a common variant near that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

}, keywords = {Alleles, Bone Morphogenetic Protein 2, Craniosynostoses, Exome, Genetic Association Studies, Humans, Infant, Mutation, Penetrance, Sequence Analysis, DNA, Smad6 Protein}, issn = {2050-084X}, doi = {10.7554/eLife.20125}, author = {Timberlake, Andrew T and Choi, Jungmin and Zaidi, Samir and Lu, Qiongshi and Nelson-Williams, Carol and Brooks, Eric D and Bilguvar, Kaya and Tikhonova, Irina and Mane, Shrikant and Yang, Jenny F and Sawh-Martinez, Rajendra and Persing, Sarah and Zellner, Elizabeth G and Loring, Erin and Chuang, Carolyn and Galm, Amy and Hashim, Peter W and Steinbacher, Derek M and DiLuna, Michael L and Duncan, Charles C and Pelphrey, Kevin A and Zhao, Hongyu and Persing, John A and Lifton, Richard P} } @article {213, title = {Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Jun}, pages = {1540-1547}, abstract = {

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

}, keywords = {Amino Acid Sequence, Cell Membrane, Child, Child, Preschool, Connexin 43, Connexins, Craniofacial Abnormalities, Disease Progression, Erythrokeratodermia Variabilis, Exome, Eye Abnormalities, Female, Foot Deformities, Congenital, Golgi Apparatus, HeLa Cells, Humans, Immunohistochemistry, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Phenotype, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Skin Diseases, Syndactyly, Tooth Abnormalities}, issn = {1523-1747}, doi = {10.1038/jid.2014.485}, author = {Boyden, Lynn M and Craiglow, Brittany G and Zhou, Jing and Hu, Ronghua and Loring, Erin C and Morel, Kimberly D and Lauren, Christine T and Lifton, Richard P and Bilguvar, Kaya and Paller, Amy S and Choate, Keith A} } @article {166, title = {Somatic V600E BRAF Mutation in Linear and Sporadic Syringocystadenoma Papilliferum.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Oct}, pages = {2536-2538}, keywords = {Biopsy, Needle, Child, Cystadenoma, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Mutation, Proto-Oncogene Proteins B-raf, Sweat Gland Neoplasms, Syringoma}, issn = {1523-1747}, doi = {10.1038/jid.2015.180}, author = {Levinsohn, Jonathan L and Sugarman, Jeffrey L and Bilguvar, Kaya and McNiff, Jennifer M and Choate, Keith A} } @article {208, title = {Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations.}, journal = {Pediatr Neurol}, volume = {51}, year = {2014}, month = {2014 Dec}, pages = {806-813.e8}, abstract = {

BACKGROUND: Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, and cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype.

METHODS: Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database.

RESULTS: We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII.

CONCLUSIONS: This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology-allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1 mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele.

}, keywords = {Adolescent, Adult, Cerebral Cortex, Collagen Type XVIII, Consanguinity, Encephalocele, Exome, Female, Fetus, Humans, Male, Mutation, Retinal Degeneration, Retinal Detachment, Young Adult}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2014.08.025}, author = {{\c C}a{\u g}layan, Ahmet Okay and Baranoski, Jacob F and Aktar, Fesih and Han, Wengi and Tuysuz, Beyhan and Guzel, Aslan and Guclu, Bulent and Kaymak{\c c}alan, Hande and Aktekin, Berrin and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Murray, Phillip B and Erson-Omay, Emine Z and Caglar, Caner and Bakircioglu, Mehmet and Sakalar, Yildirim Bayezit and Guzel, Ebru and Demir, Nihat and Tuncer, Oguz and Senturk, Senem and Ekici, Bar{\i}{\c s} and Minja, Frank J and {\v S}estan, Nenad and Yasuno, Katsuhito and Bilguvar, Kaya and Caksen, Huseyin and G{\"u}nel, Murat} } @article {268, title = {Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.}, journal = {Science}, volume = {343}, year = {2014}, month = {2014 Jan 31}, pages = {506-511}, abstract = {

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

}, keywords = {Animals, Axons, Biological Transport, Cohort Studies, Exome, Gene Regulatory Networks, Genetic Association Studies, Humans, Motor Neuron Disease, Mutation, Neurons, Nucleotides, Pyramidal Tracts, Sequence Analysis, DNA, Spastic Paraplegia, Hereditary, Synapses, Transcriptome, Zebrafish}, issn = {1095-9203}, doi = {10.1126/science.1247363}, author = {Novarino, Gaia and Fenstermaker, Ali G and Zaki, Maha S and Hofree, Matan and Silhavy, Jennifer L and Heiberg, Andrew D and Abdellateef, Mostafa and Rosti, Basak and Scott, Eric and Mansour, Lobna and Masri, Amira and Kayserili, H{\"u}lya and Al-Aama, Jumana Y and Abdel-Salam, Ghada M H and Karminejad, Ariana and Kara, Majdi and Kara, Bulent and Bozorgmehri, Bita and Ben-Omran, Tawfeg and Mojahedi, Faezeh and El Din Mahmoud, Iman Gamal and Bouslam, Naima and Bouhouche, Ahmed and Benomar, Ali and Hanein, Sylvain and Raymond, Laure and Forlani, Sylvie and Mascaro, Massimo and Selim, Laila and Shehata, Nabil and Al-Allawi, Nasir and Bindu, P S and Azam, Matloob and G{\"u}nel, Murat and Caglayan, Ahmet and Bilguvar, Kaya and Tolun, Aslihan and Issa, Mahmoud Y and Schroth, Jana and Spencer, Emily G and Rosti, Rasim O and Akizu, Naiara and Vaux, Keith K and Johansen, Anide and Koh, Alice A and Megahed, Hisham and Durr, Alexandra and Brice, Alexis and Stevanin, Giovanni and Gabriel, Stacy B and Ideker, Trey and Gleeson, Joseph G} } @article {203, title = {Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.}, journal = {Neuron}, volume = {84}, year = {2014}, month = {2014 Dec 17}, pages = {1226-39}, abstract = {

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

}, keywords = {Adenosine Triphosphatases, Animals, Brain, Cell Count, Cell Division, Dendrites, Drosophila, Drosophila Proteins, Humans, Katanin, Mice, Microcephaly, Microtubule-Associated Proteins, Mutation, Neural Stem Cells, Neurogenesis, Optic Lobe, Nonmammalian, Spindle Apparatus, Zebrafish}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.12.014}, author = {Mishra-Gorur, Ketu and {\c C}a{\u g}layan, Ahmet Okay and Schaffer, Ashleigh E and Chabu, Chiswili and Henegariu, Octavian and Vonhoff, Fernando and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Nishimura, Sayoko and Han, Wenqi and Tu, Shu and Baran, Bur{\c c}in and G{\"u}m{\"u}{\c s}, Hakan and Dilber, Cengiz and Zaki, Maha S and Hossni, Heba A A and Rivi{\`e}re, Jean-Baptiste and Kayserili, H{\"u}lya and Spencer, Emily G and Rosti, Rasim O and Schroth, Jana and Per, H{\"u}seyin and Caglar, Caner and {\c C}a{\u g}lar, {\c C}a{\u g}ri and D{\"o}len, Duygu and Baranoski, Jacob F and Kumanda{\c s}, Sefer and Minja, Frank J and Erson-Omay, E Zeynep and Mane, Shrikant M and Lifton, Richard P and Xu, Tian and Keshishian, Haig and Dobyns, William B and Chi, Neil C and {\v S}estan, Nenad and Louvi, Angeliki and Bilguvar, Kaya and Yasuno, Katsuhito and Gleeson, Joseph G and G{\"u}nel, Murat} }