@article {979, title = {Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 01}, pages = {203-207}, abstract = {

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61910}, author = {D{\textquoteright}Gama, Alissa M and England, Eleina and Madden, Jill A and Shi, JiAHi and Chao, Katherine R and Wojcik, Monica H and Torres, Alcy R and Tan, Wen-Hann and Berry, Gerard T and Prabhu, Sanjay P and Agrawal, Pankaj B} } @article {1023, title = {Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 Jun 07}, abstract = {

Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.

}, issn = {1540-9538}, doi = {10.1084/jem.20210444}, author = {Wahlster, Lara and Verboon, Jeffrey M and Ludwig, Leif S and Black, Susan C and Luo, Wendy and Garg, Kopal and Voit, Richard A and Collins, Ryan L and Garimella, Kiran and Costello, Maura and Chao, Katherine R and Goodrich, Julia K and DiTroia, Stephanie P and O{\textquoteright}Donnell-Luria, Anne and Talkowski, Michael E and Michelson, Alan D and Cantor, Alan B and Sankaran, Vijay G} } @article {806, title = {Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 10}, pages = {2272-2283}, abstract = {

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

}, keywords = {Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Male, Muscle Hypotonia, Muscle Weakness, Mutation, Missense, Myasthenic Syndromes, Congenital, Pedigree, Phenotype, Synaptic Transmission, Synaptotagmin II}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61765}, author = {Donkervoort, Sandra and Mohassel, Payam and Laugwitz, Lucia and Zaki, MAH S and Kamsteeg, Erik-Jan and Maroofian, Reza and Chao, Katherine R and Verschuuren-Bemelmans, Corien C and Horber, Veronka and Fock, Annemarie J M and McCarty, Riley M and Jain, Minal S and Biancavilla, Victoria and McMacken, Grace and Nalls, Matthew and Voermans, Nicol C and Elbendary, Hasnaa M and Snyder, Molly and Cai, Chunyu and Lehky, Tanya J and Stanley, Valentina and Iannaccone, Susan T and Foley, A Reghan and Lochm{\"u}ller, Hanns and Gleeson, Joseph and Houlden, Henry and Haack, Tobias B and Horvath, Rita and B{\"o}nnemann, Carsten G} } @article {766, title = {Expanding the phenotypic spectrum in RDH12-associated retinal disease.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {6}, year = {2020}, month = {2020 02}, abstract = {

Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in We report 15 causal alleles and expand the repertoire of known mutations with four novel variants: c.215A > G (p.Asp72Gly); c.362T > C (p.Ile121Thr); c.440A > C (p.Asn147Thr); and c.697G > A (p.Val233Ille). The broad phenotypic spectrum observed with biallelic mutations has been observed in other genetic forms of IRDs, but the diversity is particularly notable here given the prior association of primarily with severe early-onset disease. This breadth emphasizes the importance of broad genetic testing for inherited retinal disorders and extends the pool of individuals who may benefit from imminent gene-targeted therapies.

}, keywords = {Adolescent, Adult, Alcohol Oxidoreductases, Alleles, Amino Acid Substitution, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Humans, Male, Mutation, Optical Imaging, Pedigree, Phenotype, Retinal Diseases, Tomography, Optical Coherence, Whole Exome Sequencing, Young Adult}, issn = {2373-2873}, doi = {10.1101/mcs.a004754}, author = {Scott, Hilary A and Place, Emily M and Ferenchak, Kevin and Zampaglione, Erin and Wagner, Naomi E and Chao, Katherine R and DiTroia, Stephanie P and Navarro-Gomez, Daniel and Mukai, Shizuo and Huckfeldt, Rachel M and Pierce, Eric A and Bujakowska, Kinga M} } @article {713, title = {Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 02}, pages = {403-411}, abstract = {

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3{\textquoteright} splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56\% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate >=66\%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57\%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.

}, issn = {1098-1004}, doi = {10.1002/humu.23938}, author = {Bryen, Samantha J and Ewans, Lisa J and Pinner, Jason and MacLennan, Suzanna C and Donkervoort, Sandra and Castro, Diana and Topf, Ana and O{\textquoteright}Grady, Gina and Cummings, Beryl and Chao, Katherine R and Weisburd, Ben and Francioli, Laurent and Faiz, Fathimath and Bournazos, Adam M and Hu, Ying and Grosmann, Carla and Malicki, Denise M and Doyle, Helen and Witting, Nanna and Vissing, John and Claeys, Kristl G and Urankar, Kathryn and Beleza-Meireles, Ana and Baptista, Julia and Ellard, Sian and Savarese, Marco and Johari, Mridul and Vihola, Anna and Udd, Bjarne and Majumdar, Anirban and Straub, Volker and B{\"o}nnemann, Carsten G and MacArthur, Daniel G and Davis, Mark R and Cooper, Sandra T} } @article {911, title = {Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 09}, pages = {1478-1488}, abstract = {

PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.

METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.

RESULTS: We identified suspected pathogenic variants in 52\% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48\%) need further investigation.

CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

}, keywords = {Anoctamins, Exome, Glucosyltransferases, Humans, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0840-3}, author = {Topf, Ana and Johnson, Katherine and Bates, Adam and Phillips, Lauren and Chao, Katherine R and England, Eleina M and Laricchia, Kristen M and Mullen, Thomas and Valkanas, Elise and Xu, Liwen and Bertoli, Marta and Blain, Alison and Casas{\'u}s, Ana B and Duff, Jennifer and Mroczek, Magdalena and Specht, Sabine and Lek, Monkol and Ensini, Monica and MacArthur, Daniel G and Straub, Volker} } @article {567, title = {ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).}, journal = {Acta Neuropathol}, volume = {137}, year = {2019}, month = {2019 03}, pages = {501-519}, abstract = {

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.

}, issn = {1432-0533}, doi = {10.1007/s00401-019-01963-8}, author = {Lornage, Xavi{\`e}re and Romero, Norma B and Grosgogeat, Claire A and Malfatti, Edoardo and Donkervoort, Sandra and Marchetti, Michael M and Neuhaus, Sarah B and Foley, A Reghan and Labasse, Cl{\'e}mence and Schneider, Rapha{\"e}l and Carlier, Robert Y and Chao, Katherine R and Medne, Livija and Deleuze, Jean-Fran{\c c}ois and Orlikowski, David and B{\"o}nnemann, Carsten G and Gupta, Vandana A and Fardeau, Michel and B{\"o}hm, Johann and Laporte, Jocelyn} } @article {732, title = {The Genetic Landscape of Diamond-Blackfan Anemia.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 Feb 07}, pages = {356}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.011}, author = {Ulirsch, Jacob C and Verboon, Jeffrey M and Kazerounian, Shideh and Guo, Michael H and Yuan, Daniel and Ludwig, Leif S and Handsaker, Robert E and Abdulhay, Nour J and Fiorini, Claudia and Genovese, Giulio and Lim, Elaine T and Cheng, Aaron and Cummings, Beryl B and Chao, Katherine R and Beggs, Alan H and Genetti, Casie A and Sieff, Colin A and Newburger, Peter E and Niewiadomska, Edyta and Matysiak, Michal and Vlachos, Adrianna and Lipton, Jeffrey M and Atsidaftos, Eva and Glader, Bertil and Narla, Anupama and Gleizes, Pierre-Emmanuel and O{\textquoteright}Donohue, Marie-Fran{\c c}oise and Montel-Lehry, Nathalie and Amor, David J and McCarroll, Steven A and O{\textquoteright}Donnell-Luria, Anne H and Gupta, Namrata and Gabriel, Stacey B and MacArthur, Daniel G and Lander, Eric S and Lek, Monkol and Da Costa, Lydie and Nathan, David G and Korostelev, Andrei A and Do, Ron and Sankaran, Vijay G and Gazda, Hanna T} } @article {561, title = {Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations.}, journal = {Muscle Nerve}, volume = {59}, year = {2019}, month = {2019 03}, pages = {357-362}, abstract = {

INTRODUCTION: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations.

METHODS: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients.

RESULTS: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52).

CONCLUSIONS: The 2 patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve 59:357-362, 2019.

}, keywords = {Biopsy, Child, Child, Preschool, Consanguinity, Exome, Female, Genetic Association Studies, Humans, Infant, Male, Muscle Proteins, Muscle Weakness, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, Protein-Serine-Threonine Kinases, Sequence Analysis}, issn = {1097-4598}, doi = {10.1002/mus.26378}, author = {Qualls, Anita E and Donkervoort, Sandra and Herkert, Johanna C and D{\textquoteright}Gama, Alissa M and Bharucha-Goebel, Diana and Collins, James and Chao, Katherine R and Foley, A Reghan and Schoots, Mirthe H and Jongbloed, Jan D H and B{\"o}nnemann, Carsten G and Agrawal, Pankaj B} } @article {578, title = {The Genetic Landscape of Diamond-Blackfan Anemia.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {930-947}, abstract = {

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78\% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5\% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.027}, author = {Ulirsch, Jacob C and Verboon, Jeffrey M and Kazerounian, Shideh and Guo, Michael H and Yuan, Daniel and Ludwig, Leif S and Handsaker, Robert E and Abdulhay, Nour J and Fiorini, Claudia and Genovese, Giulio and Lim, Elaine T and Cheng, Aaron and Cummings, Beryl B and Chao, Katherine R and Beggs, Alan H and Genetti, Casie A and Sieff, Colin A and Newburger, Peter E and Niewiadomska, Edyta and Matysiak, Michal and Vlachos, Adrianna and Lipton, Jeffrey M and Atsidaftos, Eva and Glader, Bertil and Narla, Anupama and Gleizes, Pierre-Emmanuel and O{\textquoteright}Donohue, Marie-Fran{\c c}oise and Montel-Lehry, Nathalie and Amor, David J and McCarroll, Steven A and O{\textquoteright}Donnell-Luria, Anne H and Gupta, Namrata and Gabriel, Stacey B and MacArthur, Daniel G and Lander, Eric S and Lek, Monkol and Da Costa, Lydie and Nathan, David G and Korostelev, Andrei A and Do, Ron and Sankaran, Vijay G and Gazda, Hanna T} } @article {558, title = {MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {1009-1021}, abstract = {

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but~only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A~gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.019}, author = {Dobyns, William B and Aldinger, Kimberly A and Ishak, Gisele E and Mirzaa, Ghayda M and Timms, Andrew E and Grout, Megan E and Dremmen, Marjolein H G and Schot, Rachel and Vandervore, Laura and van Slegtenhorst, Marjon A and Wilke, Martina and Kasteleijn, Esmee and Lee, Arthur S and Barry, Brenda J and Chao, Katherine R and Szcza{\l}uba, Krzysztof and Kobori, Joyce and Hanson-Kahn, Andrea and Bernstein, Jonathan A and Carr, Lucinda and D{\textquoteright}Arco, Felice and Miyana, Kaori and Okazaki, Tetsuya and Saito, Yoshiaki and Sasaki, Masayuki and Das, Soma and Wheeler, Marsha M and Bamshad, Michael J and Nickerson, Deborah A and Engle, Elizabeth C and Verheijen, Frans W and Doherty, Dan and Mancini, Grazia M S} }