%0 Journal Article %J Brain %D 2023 %T The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders. %A Saffari, Afshin %A Lau, Tracy %A Tajsharghi, Homa %A Karimiani, Ehsan Ghayoor %A Kariminejad, Ariana %A Efthymiou, Stephanie %A Zifarelli, Giovanni %A Sultan, Tipu %A Toosi, Mehran Beiraghi %A Sedighzadeh, Sahar %A Siu, Victoria Mok %A Ortigoza-Escobar, Juan Darío %A AlShamsi, Aisha M %A Ibrahim, Shahnaz %A Al-Sannaa, Nouriya Abbas %A Al-Hertani, Walla %A Sandra, Whalen %A Tarnopolsky, Mark %A Alavi, Shahryar %A Li, Chumei %A Day-Salvatore, Debra-Lynn %A Martínez-González, Maria Jesús %A Levandoski, Kristin M %A Bedoukian, Emma %A Madan-Khetarpal, Suneeta %A Idleburg, Michaela J %A Menezes, Minal Juliet %A Siddharth, Aishwarya %A Platzer, Konrad %A Oppermann, Henry %A Smitka, Martin %A Collins, Felicity %A Lek, Monkol %A Shahrooei, Mohmmad %A Ghavideldarestani, Maryam %A Herman, Isabella %A Rendu, John %A Faure, Julien %A Baker, Janice %A Bhambhani, Vikas %A Calderwood, Laurel %A Akhondian, Javad %A Imannezhad, Shima %A Mirzadeh, Hanieh Sadat %A Hashemi, Narges %A Doosti, Mohammad %A Safi, Mojtaba %A Ahangari, Najmeh %A Torbati, Paria Najarzadeh %A Abedini, Soheila %A Salpietro, Vincenzo %A Gulec, Elif Yilmaz %A Eshaghian, Safieh %A Ghazavi, Mohammadreza %A Pascher, Michael T %A Vogel, Marina %A Abicht, Angela %A Moutton, Sebastien %A Bruel, Ange-Line %A Rieubland, Claudine %A Gallati, Sabina %A Strom, Tim M %A Lochmüller, Hanns %A Mohammadi, Mohammad Hasan %A Alvi, Javeria Raza %A Zackai, Elaine H %A Keena, Beth A %A Skraban, Cara M %A Berger, Seth I %A Andrew, Erin H %A Rahimian, Elham %A Morrow, Michelle M %A Wentzensen, Ingrid M %A Millan, Francisca %A Henderson, Lindsay B %A Dafsari, Hormos Salimi %A Jungbluth, Heinz %A Gomez-Ospina, Natalia %A McRae, Anne %A Peter, Merlene %A Veltra, Danai %A Marinakis, Nikolaos M %A Sofocleous, Christalena %A Ashrafzadeh, Farah %A Pehlivan, Davut %A Lemke, Johannes R %A Melki, Judith %A Benezit, Audrey %A Bauer, Peter %A Weis, Denisa %A James R Lupski %A Senderek, Jan %A Christodoulou, John %A Chung, Wendy K %A Goodchild, Rose %A Offiah, Amaka C %A Moreno-De-Luca, Andres %A Suri, Mohnish %A Ebrahimi-Fakhari, Darius %A Houlden, Henry %A Maroofian, Reza %K Cross-Sectional Studies %K Dystonia %K Dystonic Disorders %K Humans %K Male %K Molecular Chaperones %K Mutation %K Nervous System Malformations %K Phenotype %X

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

%B Brain %V 146 %P 3273-3288 %8 2023 Aug 01 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/36757831?dopt=Abstract %R 10.1093/brain/awad039 %0 Journal Article %J Nat Commun %D 2021 %T Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. %A Goodrich, Julia K %A Singer-Berk, Moriel %A Son, Rachel %A Sveden, Abigail %A Wood, Jordan %A England, Eleina %A Cole, Joanne B %A Weisburd, Ben %A Watts, Nick %A Caulkins, Lizz %A Dornbos, Peter %A Koesterer, Ryan %A Zappala, Zachary %A Zhang, Haichen %A Maloney, Kristin A %A Dahl, Andy %A Aguilar-Salinas, Carlos A %A Atzmon, Gil %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Blangero, John %A Eric Boerwinkle %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Centeno-Cruz, Federico %A Chambers, John C %A Chami, Nathalie %A Chan, Edmund %A Chan, Juliana %A Cheng, Ching-Yu %A Cho, Yoon Shin %A Contreras-Cubas, Cecilia %A Córdova, Emilio %A Correa, Adolfo %A DeFronzo, Ralph A %A Duggirala, Ravindranath %A Dupuis, Josée %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Gieger, Christian %A Glaser, Benjamin %A González-Villalpando, Clicerio %A Gonzalez, Ma Elena %A Grarup, Niels %A Groop, Leif %A Gross, Myron %A Haiman, Christopher %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A Heard-Costa, Nancy L %A Henderson, Brian E %A Hernandez, Juan Manuel Malacara %A Hwang, Mi Yeong %A Islas-Andrade, Sergio %A Jørgensen, Marit E %A Kang, Hyun Min %A Kim, Bong-Jo %A Kim, Young Jin %A Koistinen, Heikki A %A Kooner, Jaspal Singh %A Kuusisto, Johanna %A Kwak, Soo-Heon %A Laakso, Markku %A Lange, Leslie %A Lee, Jong-Young %A Lee, Juyoung %A Lehman, Donna M %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martínez-Hernández, Angélica %A Meigs, James B %A Meitinger, Thomas %A Mendoza-Caamal, Elvia %A Mohlke, Karen L %A Morris, Andrew D %A Morrison, Alanna C %A Ng, Maggie C Y %A Nilsson, Peter M %A O'Donnell, Christopher J %A Orozco, Lorena %A Palmer, Colin N A %A Park, Kyong Soo %A Post, Wendy S %A Pedersen, Oluf %A Preuss, Michael %A Psaty, Bruce M %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Rotter, Jerome I %A Saleheen, Danish %A Schurmann, Claudia %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Spector, Timothy D %A Strauch, Konstantin %A Strom, Tim M %A Tai, E Shyong %A Tam, Claudia H T %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tracy, Russell P %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusie-Luna, Teresa %A van Dam, Rob M %A Vasan, Ramachandran S %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Burtt, Noël P %A Zaitlen, Noah %A McCarthy, Mark I %A Boehnke, Michael %A Pollin, Toni I %A Flannick, Jason %A Mercader, Josep M %A O'Donnell-Luria, Anne %A Baxter, Samantha %A Florez, Jose C %A MacArthur, Daniel G %A Udler, Miriam S %K Adult %K Biological Variation, Population %K Biomarkers %K Diabetes Mellitus, Type 2 %K Dyslipidemias %K Exome %K Genetic Predisposition to Disease %K Genotype %K Humans %K Multifactorial Inheritance %K Penetrance %K Risk Assessment %X

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

%B Nat Commun %V 12 %P 3505 %8 2021 Jun 09 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34108472?dopt=Abstract %R 10.1038/s41467-021-23556-4 %0 Journal Article %J Nature %D 2019 %T Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. %A Flannick, Jason %A Mercader, Josep M %A Fuchsberger, Christian %A Udler, Miriam S %A Mahajan, Anubha %A Wessel, Jennifer %A Teslovich, Tanya M %A Caulkins, Lizz %A Koesterer, Ryan %A Barajas-Olmos, Francisco %A Blackwell, Thomas W %A Eric Boerwinkle %A Brody, Jennifer A %A Centeno-Cruz, Federico %A Chen, Ling %A Chen, Siying %A Contreras-Cubas, Cecilia %A Córdova, Emilio %A Correa, Adolfo %A Cortes, Maria %A DeFronzo, Ralph A %A Dolan, Lawrence %A Drews, Kimberly L %A Elliott, Amanda %A Floyd, James S %A Gabriel, Stacey %A Garay-Sevilla, Maria Eugenia %A García-Ortiz, Humberto %A Gross, Myron %A Han, Sohee %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jørgensen, Marit E %A Kang, Hyun Min %A Kelsey, Megan %A Kim, Bong-Jo %A Koistinen, Heikki A %A Kuusisto, Johanna %A Leader, Joseph B %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Lyssenko, Valeriya %A Manning, Alisa K %A Marcketta, Anthony %A Malacara-Hernandez, Juan Manuel %A Martínez-Hernández, Angélica %A Matsuo, Karen %A Mayer-Davis, Elizabeth %A Mendoza-Caamal, Elvia %A Mohlke, Karen L %A Morrison, Alanna C %A Ndungu, Anne %A Ng, Maggie C Y %A O'Dushlaine, Colm %A Payne, Anthony J %A Pihoker, Catherine %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rayner, N William %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Robertson, Neil R %A Santoro, Nicola %A Schurmann, Claudia %A So, Wing Yee %A Soberón, Xavier %A Stringham, Heather M %A Strom, Tim M %A Tam, Claudia H T %A Thameem, Farook %A Tomlinson, Brian %A Torres, Jason M %A Tracy, Russell P %A van Dam, Rob M %A Vujkovic, Marijana %A Wang, Shuai %A Welch, Ryan P %A Witte, Daniel R %A Wong, Tien-Yin %A Atzmon, Gil %A Barzilai, Nir %A Blangero, John %A Bonnycastle, Lori L %A Bowden, Donald W %A Chambers, John C %A Chan, Edmund %A Cheng, Ching-Yu %A Cho, Yoon Shin %A Collins, Francis S %A de Vries, Paul S %A Duggirala, Ravindranath %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez, Ma Elena %A Groop, Leif %A Kooner, Jaspal Singh %A Kwak, Soo Heon %A Laakso, Markku %A Lehman, Donna M %A Nilsson, Peter %A Spector, Timothy D %A Tai, E Shyong %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wilson, James G %A Aguilar-Salinas, Carlos A %A Bottinger, Erwin %A Burke, Brian %A Carey, David J %A Chan, Juliana C N %A Dupuis, Josée %A Frossard, Philippe %A Heckbert, Susan R %A Hwang, Mi Yeong %A Kim, Young Jin %A Kirchner, H Lester %A Lee, Jong-Young %A Lee, Juyoung %A Loos, Ruth J F %A Ma, Ronald C W %A Morris, Andrew D %A O'Donnell, Christopher J %A Palmer, Colin N A %A Pankow, James %A Park, Kyong Soo %A Rasheed, Asif %A Saleheen, Danish %A Sim, Xueling %A Small, Kerrin S %A Teo, Yik Ying %A Haiman, Christopher %A Hanis, Craig L %A Henderson, Brian E %A Orozco, Lorena %A Tusie-Luna, Teresa %A Dewey, Frederick E %A Baras, Aris %A Gieger, Christian %A Meitinger, Thomas %A Strauch, Konstantin %A Lange, Leslie %A Grarup, Niels %A Hansen, Torben %A Pedersen, Oluf %A Zeitler, Philip %A Dabelea, Dana %A Abecasis, Goncalo %A Bell, Graeme I %A Cox, Nancy J %A Seielstad, Mark %A Sladek, Rob %A Meigs, James B %A Rich, Steve S %A Rotter, Jerome I %A Altshuler, David %A Burtt, Noël P %A Scott, Laura J %A Morris, Andrew P %A Florez, Jose C %A McCarthy, Mark I %A Boehnke, Michael %K Animals %K Case-Control Studies %K Decision Support Techniques %K Diabetes Mellitus, Type 2 %K Exome %K Exome Sequencing %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Male %K Mice %K Mice, Knockout %X

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

%B Nature %V 570 %P 71-76 %8 2019 Jun %G eng %N 7759 %1 https://www.ncbi.nlm.nih.gov/pubmed/31118516?dopt=Abstract %R 10.1038/s41586-019-1231-2 %0 Journal Article %J Am J Hum Genet %D 2017 %T De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. %A Lessel, Davor %A Schob, Claudia %A Küry, Sébastien %A Reijnders, Margot R F %A Harel, Tamar %A Eldomery, Mohammad K %A Coban-Akdemir, Zeynep %A Denecke, Jonas %A Edvardson, Shimon %A Colin, Estelle %A Stegmann, Alexander P A %A Gerkes, Erica H %A Tessarech, Marine %A Bonneau, Dominique %A Barth, Magalie %A Besnard, Thomas %A Cogné, Benjamin %A Revah-Politi, Anya %A Strom, Tim M %A Rosenfeld, Jill A %A Yang, Yaping %A Posey, Jennifer E %A Immken, Ladonna %A Oundjian, Nelly %A Helbig, Katherine L %A Meeks, Naomi %A Zegar, Kelsey %A Morton, Jenny %A Schieving, Jolanda H %A Claasen, Ana %A Huentelman, Matthew %A Narayanan, Vinodh %A Ramsey, Keri %A Brunner, Han G %A Elpeleg, Orly %A Mercier, Sandra %A Bézieau, Stéphane %A Kubisch, Christian %A Kleefstra, Tjitske %A Kindler, Stefan %A Lupski, James R %A Kreienkamp, Hans-Jürgen %K Adenosine Triphosphatases %K Adolescent %K Amino Acids %K Cell Line %K Cell Line, Tumor %K Central Nervous System %K Child %K Child, Preschool %K Developmental Disabilities %K Female %K HEK293 Cells %K Humans %K Intellectual Disability %K Male %K Mutation, Missense %K RNA %K RNA Helicases %X

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

%B Am J Hum Genet %V 101 %P 716-724 %8 2017 Nov 02 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29100085?dopt=Abstract %R 10.1016/j.ajhg.2017.09.014