@article {656, title = {Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Mar}, pages = {257-269}, abstract = {

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60\%) or its homologous EP300 (~ 10\%). No causative mutation is identified in up to 30\% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.

}, keywords = {Child, Child, Preschool, Comparative Genomic Hybridization, CREB-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Genetic, Facies, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Rubinstein-Taybi Syndrome, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-01985-y}, author = {Negri, Gloria and Magini, Pamela and Milani, Donatella and Crippa, Milena and Biamino, Elisa and Piccione, Maria and Sotgiu, Stefano and Perr{\`\i}a, Chiara and Vitiello, Giuseppina and Frontali, Marina and Boni, Antonella and Di Fede, Elisabetta and Gandini, Maria Chiara and Colombo, Elisa Adele and Bamshad, Michael J and Nickerson, Deborah A and Smith, Joshua D and Loddo, Italia and Finelli, Palma and Seri, Marco and Pippucci, Tommaso and Larizza, Lidia and Gervasini, Cristina} } @article {474, title = {Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1143-1157}, abstract = {

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14\% of multi-affected families and 2\% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Biotinylation, Cadherins, Catenins, Cleft Lip, Cleft Palate, Epithelium, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Palate, Pedigree, Syndrome, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.009}, author = {Cox, Liza L and Cox, Timothy C and Moreno Uribe, Lina M and Zhu, Ying and Richter, Chika T and Nidey, Nichole and Standley, Jennifer M and Deng, Mei and Blue, Elizabeth and Chong, Jessica X and Yang, Yueqin and Carstens, Russ P and Anand, Deepti and Lachke, Salil A and Smith, Joshua D and Dorschner, Michael O and Bedell, Bruce and Kirk, Edwin and Hing, Anne V and Venselaar, Hanka and Valencia-Ramirez, Luz C and Bamshad, Michael J and Glass, Ian A and Cooper, Jonathan A and Haan, Eric and Nickerson, Deborah A and van Bokhoven, Hans and Zhou, Huiqing and Krahn, Katy N and Buckley, Michael F and Murray, Jeffrey C and Lidral, Andrew C and Roscioli, Tony} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {204, title = {Challenges and solutions for gene identification in the presence of familial locus heterogeneity.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Sep}, pages = {1207-15}, abstract = {

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25\% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3\% (95\% confidence interval: 11.9\%, 19.9\%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

}, keywords = {Asian Continental Ancestry Group, Calcium-Binding Proteins, Chromosome Mapping, Connexin 26, Connexins, Consanguinity, European Continental Ancestry Group, Female, Genes, Recessive, Genetic Heterogeneity, Genetic Linkage, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genotype, Hearing Loss, Hepatocyte Growth Factor, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Membrane Transport Proteins, Mutation, Pedigree, Phenotype, Sulfate Transporters}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.266}, author = {Rehman, Atteeq U and Santos-Cortez, Regie Lyn P and Drummond, Meghan C and Shahzad, Mohsin and Lee, Kwanghyuk and Morell, Robert J and Ansar, Muhammad and Jan, Abid and Wang, Xin and Aziz, Abdul and Riazuddin, Saima and Smith, Joshua D and Wang, Gao T and Ahmed, Zubair M and Gul, Khitab and Shearer, A Eliot and Smith, Richard J H and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hinnant, John and Khan, Shaheen N and Fisher, Rachel A and Ahmad, Wasim and Friderici, Karen H and Riazuddin, Sheikh and Friedman, Thomas B and Wilch, Ellen S and Leal, Suzanne M} } @article {227, title = {Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {235-40}, abstract = {

Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Craniofacial Abnormalities, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Face, Hedgehog Proteins, Humans, Intellectual Disability, Limb Deformities, Congenital, Mandibulofacial Dysostosis, Mice, Molecular Sequence Data, Mutation, Protein Structure, Tertiary, Zebrafish, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.008}, author = {Smith, Joshua D and Hing, Anne V and Clarke, Christine M and Johnson, Nathan M and Perez, Francisco A and Park, Sarah S and Horst, Jeremy A and Mecham, Brig and Maves, Lisa and Nickerson, Deborah A and Cunningham, Michael L} } @article {256, title = {Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {734-44}, abstract = {

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83\%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82\%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher{\textquoteright}s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

}, keywords = {Abnormalities, Multiple, Arachnodactyly, Arthrogryposis, Blepharophimosis, Child, Child, Preschool, Cleft Palate, Clubfoot, Connective Tissue Diseases, Contracture, Exome, Female, Hand Deformities, Congenital, Humans, Ion Channels, Male, Mutation, Ophthalmoplegia, Pedigree, Retinal Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.03.015}, author = {McMillin, Margaret J and Beck, Anita E and Chong, Jessica X and Shively, Kathryn M and Buckingham, Kati J and Gildersleeve, Heidi I S and Aracena, Mariana I and Aylsworth, Arthur S and Bitoun, Pierre and Carey, John C and Clericuzio, Carol L and Crow, Yanick J and Curry, Cynthia J and Devriendt, Koenraad and Everman, David B and Fryer, Alan and Gibson, Kate and Giovannucci Uzielli, Maria Luisa and Graham, John M and Hall, Judith G and Hecht, Jacqueline T and Heidenreich, Randall A and Hurst, Jane A and Irani, Sarosh and Krapels, Ingrid P C and Leroy, Jules G and Mowat, David and Plant, Gordon T and Robertson, Stephen P and Schorry, Elizabeth K and Scott, Richard H and Seaver, Laurie H and Sherr, Elliott and Splitt, Miranda and Stewart, Helen and Stumpel, Constance and Temel, Sehime G and Weaver, David D and Whiteford, Margo and Williams, Marc S and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {260, title = {Mutations in TJP2 cause progressive cholestatic liver disease.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Apr}, pages = {326-8}, abstract = {

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

}, keywords = {Animals, Base Sequence, Cholestasis, Intrahepatic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Biological, Molecular Sequence Data, Mutation, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Alignment, Species Specificity, Tight Junctions, Zonula Occludens-2 Protein}, issn = {1546-1718}, doi = {10.1038/ng.2918}, author = {Sambrotta, Melissa and Strautnieks, Sandra and Papouli, Efterpi and Rushton, Peter and Clark, Barnaby E and Parry, David A and Logan, Clare V and Newbury, Lucy J and Kamath, Binita M and Ling, Simon and Grammatikopoulos, Tassos and Wagner, Bart E and Magee, John C and Sokol, Ronald J and Mieli-Vergani, Giorgina and Smith, Joshua D and Johnson, Colin A and McClean, Patricia and Simpson, Michael A and Knisely, A S and Bull, Laura N and Thompson, Richard J} } @article {254, title = {TCIRG1-associated congenital neutropenia.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Jul}, pages = {824-7}, abstract = {

Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30\% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.

}, keywords = {DNA Mutational Analysis, Heterozygote, Humans, Mutation, Neutropenia, Pedigree, Vacuolar Proton-Translocating ATPases}, issn = {1098-1004}, doi = {10.1002/humu.22563}, author = {Makaryan, Vahagn and Rosenthal, Elisabeth A and Bolyard, Audrey Anna and Kelley, Merideth L and Below, Jennifer E and Bamshad, Michael J and Bofferding, Kathryn M and Smith, Joshua D and Buckingham, Kati and Boxer, Laurence A and Skokowa, Julia and Welte, Karl and Nickerson, Deborah A and Jarvik, Gail P and Dale, David C} } @article {305, title = {Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {632-6}, abstract = {

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

}, keywords = {Biological Transport, Case-Control Studies, Child, Child, Preschool, Congenital Disorders of Glycosylation, Exome, Female, Glycosylation, Humans, Male, Monosaccharide Transport Proteins, Mosaicism, Mutation, Spectrometry, Mass, Electrospray Ionization, Transferrin, Uridine Diphosphate Galactose}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.012}, author = {Ng, Bobby G and Buckingham, Kati J and Raymond, Kimiyo and Kircher, Martin and Turner, Emily H and He, Miao and Smith, Joshua D and Eroshkin, Alexey and Szybowska, Marta and Losfeld, Marie E and Chong, Jessica X and Kozenko, Mariya and Li, Chumei and Patterson, Marc C and Gilbert, Rodney D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Freeze, Hudson H} } @article {313, title = {Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {137-43}, abstract = {

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60\% of cases overall, including both of the families in our cohort with more than one affected child and 50\% of the simplex cases.

}, keywords = {Child, Child, Preschool, Female, Genome, Human, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.011}, author = {Below, Jennifer E and Earl, Dawn L and Shively, Kathryn M and McMillin, Margaret J and Smith, Joshua D and Turner, Emily H and Stephan, Mark J and Al-Gazali, Lihadh I and Hertecant, Jozef L and Chitayat, David and Unger, Sheila and Cohn, Daniel H and Krakow, Deborah and Swanson, James M and Faustman, Elaine M and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }