@article {396, title = {A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Aug}, pages = {2246-2250}, abstract = {

GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5{\textquoteright}-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.

}, keywords = {Abnormalities, Multiple, Child, Child, Preschool, Craniofacial Abnormalities, Epilepsy, Exome, Facies, Female, Heterozygote, Humans, Intellectual Disability, Microcephaly, Muscular Atrophy, Mutation, Missense, Nucleotidyltransferases, Pedigree, Phenotype, Seizures}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38292}, author = {Gold, Wendy A and Sobreira, Nara and Wiame, Elsa and Marbaix, Alexandre and Van Schaftingen, Emile and Franzka, Patricia and Riley, Lisa G and Worgan, Lisa and H{\"u}bner, Christian A and Christodoulou, John and Ad{\`e}s, Lesley C} } @article {433, title = {Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 12}, pages = {1335-1344}, abstract = {

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

}, keywords = {Abnormalities, Multiple, Case-Control Studies, Child, DNA Methylation, Face, Female, Hematologic Diseases, Histone-Lysine N-Methyltransferase, Humans, Loss of Function Mutation, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Vestibular Diseases}, issn = {1476-5438}, doi = {10.1038/s41431-017-0023-0}, author = {Sobreira, Nara and Brucato, Martha and Zhang, Li and Ladd-Acosta, Christine and Ongaco, Chrissie and Romm, Jane and Doheny, Kimberly F and Mingroni-Netto, Regina C and Bertola, D{\'e}bora and Kim, Chong A and Perez, Ana Ba and Melaragno, Maria I and Valle, David and Meloni, Vera A and Bjornsson, Hans T} } @article {417, title = {Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 07}, pages = {1934-7}, abstract = {

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM\%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Abnormalities, Multiple, Base Sequence, Child, Preschool, Coloboma, DNA-Binding Proteins, Exome, Eyelid Neoplasms, Female, Frameshift Mutation, Genomic Imprinting, Humans, Lipoma, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37683}, author = {Chac{\'o}n-Camacho, Oscar F and Sobreira, Nara and You, Jing and Pi{\~n}a-Aguilar, Raul E and Villegas-Ruiz, Vanessa and Zenteno, Juan C} } @article {126, title = {Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {156-61}, abstract = {

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, DNA-Binding Proteins, Exome, Face, Female, Hand Deformities, Congenital, Heterozygote, Humans, Intellectual Disability, Male, Micrognathism, Mosaicism, Mutation, Neck, Pedigree, Siblings, Transcription Factors}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37405}, author = {Ben-Salem, Salma and Sobreira, Nara and Akawi, Nadia A and Al-Shamsi, Aisha M and John, Anne and Pramathan, Thachillath and Valle, David and Ali, Bassam R and Al-Gazali, Lihadh} } @article {416, title = {Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 11}, pages = {2965-2974}, abstract = {

Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Abnormalities, Multiple, Actins, Child, Preschool, Colon, Consanguinity, DNA Mutational Analysis, Fatal Outcome, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Intestinal Pseudo-Obstruction, Male, Mutation, Phenotype, Polymorphism, Single Nucleotide, Treatment Outcome, Ultrasonography, Prenatal, Urinary Bladder}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37857}, author = {Moreno, Carolina Araujo and Metze, Konradin and Lomazi, Elizete Aparecida and Bertola, D{\'e}bora Romeo and Barbosa, Ricardo Henrique Almeida and Cosentino, Viviana and Sobreira, Nara and Cavalcanti, Denise Pontes} } @article {146, title = {GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1009-1014}, abstract = {

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, Craniofacial Abnormalities, Databases, Genetic, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein K, Humans, Information Dissemination, Intellectual Disability, Male, Muscular Atrophy, Phenotype, Polymorphism, Single Nucleotide, Ribonucleoproteins, Software, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22837}, author = {Au, P Y Billie and You, Jing and Caluseriu, Oana and Schwartzentruber, Jeremy and Majewski, Jacek and Bernier, Francois P and Ferguson, Marcia and Valle, David and Parboosingh, Jillian S and Sobreira, Nara and Innes, A Micheil and Kline, Antonie D} } @article {130, title = {Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Sep 03}, pages = {457-64}, abstract = {

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Base Sequence, Exome, Female, Gene Frequency, Genes, Recessive, Hearing Loss, Homeodomain Proteins, Humans, Intellectual Disability, Male, Microcephaly, Molecular Sequence Data, Mutation, Seizures, Sequence Alignment, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.07.014}, author = {Tanaka, Akemi J and Cho, Megan T and Millan, Francisca and Juusola, Jane and Retterer, Kyle and Joshi, Charuta and Niyazov, Dmitriy and Garnica, Adolfo and Gratz, Edward and Deardorff, Matthew and Wilkins, Alisha and Ortiz-Gonzalez, Xilma and Mathews, Katherine and Panzer, Karin and Brilstra, Eva and van Gassen, Koen L I and Volker-Touw, Catharina M L and van Binsbergen, Ellen and Sobreira, Nara and Hamosh, Ada and McKnight, Dianalee and Monaghan, Kristin G and Chung, Wendy K} }