@article {952, title = {Typical achondroplasia secondary to a unique insertional variant of FGFR3 with in vitro demonstration of its effect on FGFR3 function.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {798-805}, abstract = {

We describe an individual in whom clinical and radiographic features are typical for achondroplasia, but in whom the common variants of FGFR3 that result in achondroplasia are absent. Whole exome sequencing demonstrated a novel, de novo 6 base pair tandem duplication in FGFR3 that results in the insertion of Ser-Phe after position Leu324. in vitro studies showed that this variant results in aberrant dimerization, excessive spontaneous phosphorylation of FGFR3 dimers and excessive, ligand-independent tyrosine kinase activity. Together, these data suggest that this variant leads to constitutive disulfide bond-mediated dimerization, and that this, surprisingly, occurs to an extent similar to the neonatal lethal thanatophoric dysplasia type I Ser249Cys variant.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62043}, author = {Meyer, April N and Modaff, Peggy and Wang, Clark G and Wohler, Elizabeth and Sobreira, Nara L and Donoghue, Daniel J and Pauli, Richard M} } @article {964, title = {Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.}, journal = {Hum Mol Genet}, volume = {29}, year = {2020}, month = {2020 12 04}, pages = {3662-3678}, abstract = {

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddaa258}, author = {Martin, Ella M M A and Enriquez, Annabelle and Sparrow, Duncan B and Humphreys, David T and McInerney-Leo, Aideen M and Leo, Paul J and Duncan, Emma L and Iyer, Kavitha R and Greasby, Joelene A and Ip, Eddie and Giannoulatou, Eleni and Sheng, Delicia and Wohler, Elizabeth and Dimartino, Cl{\'e}mantine and Amiel, Jeanne and Capri, Yline and Lehalle, Daphn{\'e} and Mory, Adi and Wilnai, Yael and Lebenthal, Yael and Gharavi, Ali G and Krzemie{\'n}, Gra{\.z}yna G and Miklaszewska, Monika and Steiner, Robert D and Raggio, Cathy and Blank, Robert and Baris Feldman, Hagit and Milo Rasouly, Hila and Sobreira, Nara L M and Jobling, Rebekah and Gordon, Christopher T and Giampietro, Philip F and Dunwoodie, Sally L and Chapman, Gavin} } @article {778, title = {KIAA1217: A novel candidate gene associated with isolated and syndromic vertebral malformations.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 07}, pages = {1664-1672}, abstract = {

Vertebral malformations (VMs) are caused by alterations in somitogenesis and may occur in association with other congenital anomalies. The genetic etiology of most VMs remains unknown and their identification may facilitate the development of novel therapeutic and prevention strategies. Exome sequencing was performed on both the discovery cohort of nine unrelated probands from the USA with VMs and the replication cohort from China (Deciphering Disorders Involving Scoliosis \& COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool. Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and other annotations to identify the best candidates. Genes with candidate variants in three or more probands were selected. The replication cohort was analyzed by another in-house developed pipeline. We identified rare heterozygous variants in KIAA1217 in four out of nine probands in the discovery cohort and in five out of 35 probands in the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in 10 probands, three of which have not been described in gnomAD and one of which is a nonsense variant. We propose that genetic variations of KIAA1217 may contribute to the etiology of VMs.

}, keywords = {Adolescent, Cervical Vertebrae, Child, Codon, Nonsense, Databases, Genetic, Female, Heterozygote, Homozygote, Humans, Male, Proteins, Spinal Diseases, Thoracic Vertebrae}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61607}, author = {Al Dhaheri, Noura and Wu, Nan and Zhao, Sen and Wu, Zhihong and Blank, Robert D and Zhang, Jianguo and Raggio, Cathy and Halanski, Matthew and Shen, Jianxiong and Noonan, Ken and Qiu, Guixing and Nemeth, Blaise and Sund, Sarah and Dunwoodie, Sally L and Chapman, Gavin and Glurich, Ingrid and Steiner, Robert D and Wohler, Elizabeth and Martin, Renan and Sobreira, Nara Lygia and Giampietro, Philip F} } @article {939, title = {A novel homozygous KY variant causing a complex neurological disorder.}, journal = {Eur J Med Genet}, volume = {63}, year = {2020}, month = {2020 Nov}, pages = {104031}, abstract = {

Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a complex neurological phenotype in a consanguineous Pakistani family with four affected members, manifesting lower limb spasticity and weakness, toe walking, pes equinovarus, and a speech disorder. Genome-wide linkage analysis with microsatellite markers delineated chromosome 3q22.2-q24 harboring the disease gene. Whole exome sequencing was performed for two subjects, identifying a homozygous 14-bp frameshift deletion NM_178554.6:c.842_855del; p(Val281GlyfsTer18) in KY. The variant segregated with the phenotype and was absent from public databases and 100 ethnically matched controls. We confirm a novel homozygous KY variant causing a complex neurological phenotype in this family. A review of previously reported KY variants suggests that variants in this gene can cause a spectrum of neurological phenotypes.

}, keywords = {Child, Female, Frameshift Mutation, Gait, Homozygote, Humans, Male, Myopathies, Structural, Congenital, Pedigree, Peptide Hydrolases, Phenotype, Spastic Paraplegia, Hereditary, Speech}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2020.104031}, author = {Arif, Beenish and Rasheed, Arisha and Kumar, Kishore R and Fatima, Amara and Abbas, Ghazanfar and Wohler, Elizabeth and Sobriera, Nara and Lohmann, Katja and Naz, Sadaf} } @article {912, title = {Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 07}, pages = {1215-1226}, abstract = {

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.

RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.

CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

}, keywords = {Exome, Germ Cells, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Transcriptome, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins}, issn = {1530-0366}, doi = {10.1038/s41436-020-0792-7}, author = {Castilla-Vallmanya, Laura and Selmer, Kaja K and Dimartino, Cl{\'e}mantine and Rabionet, Raquel and Blanco-S{\'a}nchez, Bernardo and Yang, Sandra and Reijnders, Margot R F and van Essen, Antonie J and Oufadem, Myriam and Vigeland, Magnus D and Stadheim, Barbro and Houge, Gunnar and Cox, Helen and Kingston, Helen and Clayton-Smith, Jill and Innis, Jeffrey W and Iascone, Maria and Cereda, Anna and Gabbiadini, Sara and Chung, Wendy K and Sanders, Victoria and Charrow, Joel and Bryant, Emily and Millichap, John and Vitobello, Antonio and Thauvin, Christel and Mau-Them, Frederic Tran and Faivre, Laurence and Lesca, Gaetan and Labalme, Audrey and Rougeot, Christelle and Chatron, Nicolas and Sanlaville, Damien and Christensen, Katherine M and Kirby, Amelia and Lewandowski, Raymond and Gannaway, Rachel and Aly, MAH and Lehman, Anna and Clarke, Lorne and Graul-Neumann, Luitgard and Zweier, Christiane and Lessel, Davor and Lozic, Bernarda and Aukrust, Ingvild and Peretz, Ryan and Stratton, Robert and Smol, Thomas and Dieux-Co{\"e}slier, Anne and Meira, Joanna and Wohler, Elizabeth and Sobreira, Nara and Beaver, Erin M and Heeley, Jennifer and Briere, Lauren C and High, Frances A and Sweetser, David A and Walker, Melissa A and Keegan, Catherine E and Jayakar, Parul and Shinawi, Marwan and Kerstjens-Frederikse, Wilhelmina S and Earl, Dawn L and Siu, Victoria M and Reesor, Emma and Yao, Tony and Hegele, Robert A and Vaske, Olena M and Rego, Shannon and Shapiro, Kevin A and Wong, Brian and Gambello, Michael J and McDonald, Marie and Karlowicz, Danielle and Colombo, Roberto and Serretti, Alessandro and Pais, Lynn and O{\textquoteright}Donnell-Luria, Anne and Wray, Alison and Sadedin, Simon and Chong, Belinda and Tan, Tiong Y and Christodoulou, John and White, Susan M and Slavotinek, Anne and Barbouth, Deborah and Morel Swols, Dayna and Parisot, M{\'e}lanie and Bole-Feysot, Christine and Nitschk{\'e}, Patrick and Pingault, V{\'e}ronique and Munnich, Arnold and Cho, Megan T and Cormier-Daire, Val{\'e}rie and Balcells, Susanna and Lyonnet, Stanislas and Grinberg, Daniel and Amiel, Jeanne and Urreizti, Roser and Gordon, Christopher T} } @article {768, title = {The utility of exome sequencing for fetal pleural effusions.}, journal = {Prenat Diagn}, volume = {40}, year = {2020}, month = {2020 04}, pages = {590-595}, abstract = {

OBJECTIVE: We sought to evaluate the performance of exome sequencing (ES) in determining an underlying genetic etiology for cases of fetal pleural effusions.

STUDY DESIGN: We examined a prospective cohort series of fetal pleural effusions visualized sonographically between 1 April 2016 and 31 August 2017. Fetal pleural effusions attributed to twin sharing, anemia, or structural anomalies were excluded, as were all cases with a genetic diagnosis established by karyotype or chromosomal microarray analysis. The remaining cases with pleural effusions of unclear etiology were offered ES. ES was performed by clinical sequencing and/or sequencing under the Baylor-Hopkins Center for Mendelian Genomics{\textquoteright} (BHCMG) research platform. All cases were evaluated for novel genes or phenotypic expansion of disease-causing genes.

RESULTS: ES was performed on six probands affected by pleural effusions. A pathogenic variant was identified in one case (16.7\%). Four additional cases had variants of uncertain significance (VUS) in candidate genes of pathological interest. Neither clinical nor candidate genes were evident in the final case.

CONCLUSION: ES should be considered in the evaluation of prenatally detected idiopathic pleural effusions when other diagnostic workup for a genetic etiology has failed.

}, issn = {1097-0223}, doi = {10.1002/pd.5650}, author = {Jelin, Angie C and Sobreira, Nara and Wohler, Elizabeth and Solomon, Benjamin and Sparks, Teresa and Sagaser, Katelynn G and Forster, Katherine R and Miller, Jena and Witmer, P Dane and Hamosh, Ada and Valle, David and Blakemore, Karin} } @article {585, title = {Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.}, journal = {J Clin Invest}, volume = {129}, year = {2019}, month = {2019 Mar 01}, pages = {1240-1256}, abstract = {

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients{\textquoteright} fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

}, issn = {1558-8238}, doi = {10.1172/JCI123959}, author = {Pant, Devesh C and Dorboz, Imen and Schluter, Agatha and Fourcade, St{\'e}phane and Launay, Nathalie and Joya, Javier and Aguilera-Albesa, Sergio and Yoldi, Maria Eugenia and Casasnovas, Carlos and Willis, Mary J and Ruiz, Montserrat and Ville, Doroth{\'e}e and Lesca, Gaetan and Siquier-Pernet, Karine and Desguerre, Isabelle and Yan, Huifang and Wang, Jingmin and Burmeister, Margit and Brady, Lauren and Tarnopolsky, Mark and Cornet, Carles and Rubbini, Davide and Terriente, Javier and James, Kiely N and Musaev, Damir and Zaki, Maha S and Patterson, Marc C and Lanpher, Brendan C and Klee, Eric W and Pinto E Vairo, Filippo and Wohler, Elizabeth and Sobreira, Nara Lygia de M and Cohen, Julie S and Maroofian, Reza and Galehdari, Hamid and Mazaheri, Neda and Shariati, Gholamreza and Colleaux, Laurence and Rodriguez, Diana and Gleeson, Joseph G and Pujades, Cristina and Fatemi, Ali and Boespflug-Tanguy, Odile and Pujol, Aurora} }