%0 Journal Article %J Am J Hum Genet %D 2017 %T De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder. %A Küry, Sébastien %A Besnard, Thomas %A Ebstein, Frédéric %A Khan, Tahir N %A Gambin, Tomasz %A Douglas, Jessica %A Bacino, Carlos A %A Craigen, William J %A Sanders, Stephan J %A Lehmann, Andrea %A Latypova, Xénia %A Khan, Kamal %A Pacault, Mathilde %A Sacharow, Stephanie %A Glaser, Kimberly %A Bieth, Eric %A Perrin-Sabourin, Laurence %A Jacquemont, Marie-Line %A Cho, Megan T %A Roeder, Elizabeth %A Denommé-Pichon, Anne-Sophie %A Monaghan, Kristin G %A Yuan, Bo %A Xia, Fan %A Simon, Sylvain %A Bonneau, Dominique %A Parent, Philippe %A Gilbert-Dussardier, Brigitte %A Odent, Sylvie %A Toutain, Annick %A Pasquier, Laurent %A Barbouth, Deborah %A Shaw, Chad A %A Patel, Ankita %A Smith, Janice L %A Bi, Weimin %A Schmitt, Sébastien %A Deb, Wallid %A Nizon, Mathilde %A Mercier, Sandra %A Vincent, Marie %A Rooryck, Caroline %A Malan, Valérie %A Briceño, Ignacio %A Gómez, Alberto %A Nugent, Kimberly M %A Gibson, James B %A Cogné, Benjamin %A Lupski, James R %A Stessman, Holly A F %A Eichler, Evan E %A Retterer, Kyle %A Yang, Yaping %A Redon, Richard %A Katsanis, Nicholas %A Rosenfeld, Jill A %A Kloetzel, Peter-Michael %A Golzio, Christelle %A Bézieau, Stéphane %A Stankiewicz, Paweł %A Isidor, Bertrand %K Adolescent %K Animals %K Child %K Child, Preschool %K Disease Models, Animal %K DNA Copy Number Variations %K Down-Regulation %K Female %K Gene Deletion %K Humans %K Infant %K Intellectual Disability %K Male %K Microcephaly %K Neurodevelopmental Disorders %K Polymorphism, Single Nucleotide %K Proteasome Endopeptidase Complex %K Zebrafish %X

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

%B Am J Hum Genet %V 100 %P 352-363 %8 2017 Feb 02 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/28132691?dopt=Abstract %R 10.1016/j.ajhg.2017.01.003 %0 Journal Article %J Genet Med %D 2017 %T Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene. %A Bekheirnia, Mir Reza %A Bekheirnia, Nasim %A Bainbridge, Matthew N %A Gu, Shen %A Coban Akdemir, Zeynep Hande %A Gambin, Tomek %A Janzen, Nicolette K %A Jhangiani, Shalini N %A Muzny, Donna M %A Michael, Mini %A Brewer, Eileen D %A Elenberg, Ewa %A Kale, Arundhati S %A Riley, Alyssa A %A Swartz, Sarah J %A Scott, Daryl A %A Yang, Yaping %A Srivaths, Poyyapakkam R %A Wenderfer, Scott E %A Bodurtha, Joann %A Applegate, Carolyn D %A Velinov, Milen %A Myers, Angela %A Borovik, Lior %A Craigen, William J %A Hanchard, Neil A %A Rosenfeld, Jill A %A Lewis, Richard Alan %A Gonzales, Edmond T %A Gibbs, Richard A %A Belmont, John W %A Roth, David R %A Eng, Christine %A Braun, Michael C %A Lupski, James R %A Lamb, Dolores J %K Adolescent %K Child %K Child, Preschool %K DNA Copy Number Variations %K Exome Sequencing %K Female %K Forkhead Transcription Factors %K Genetic Predisposition to Disease %K Hepatocyte Nuclear Factor 1-beta %K Humans %K Infant %K Intracellular Signaling Peptides and Proteins %K Male %K Nuclear Proteins %K PAX2 Transcription Factor %K Pedigree %K Polymorphism, Single Nucleotide %K Protein Tyrosine Phosphatases %K Repressor Proteins %K Urogenital Abnormalities %K Vesico-Ureteral Reflux %K Young Adult %X

PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

RESULTS: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

%B Genet Med %V 19 %P 412-420 %8 2017 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/27657687?dopt=Abstract %R 10.1038/gim.2016.131 %0 Journal Article %J JAMA %D 2014 %T Molecular findings among patients referred for clinical whole-exome sequencing. %A Yang, Yaping %A Muzny, Donna M %A Xia, Fan %A Niu, Zhiyv %A Person, Richard %A Ding, Yan %A Ward, Patricia %A Braxton, Alicia %A Wang, Min %A Buhay, Christian %A Veeraraghavan, Narayanan %A Hawes, Alicia %A Chiang, Theodore %A Leduc, Magalie %A Beuten, Joke %A Zhang, Jing %A He, Weimin %A Scull, Jennifer %A Willis, Alecia %A Landsverk, Megan %A Craigen, William J %A Bekheirnia, Mir Reza %A Stray-Pedersen, Asbjorg %A Liu, Pengfei %A Wen, Shu %A Alcaraz, Wendy %A Cui, Hong %A Walkiewicz, Magdalena %A Reid, Jeffrey %A Bainbridge, Matthew %A Patel, Ankita %A Boerwinkle, Eric %A Beaudet, Arthur L %A Lupski, James R %A Plon, Sharon E %A Gibbs, Richard A %A Eng, Christine M %K Adolescent %K Adult %K Child %K Child, Preschool %K Exome %K Female %K Fetus %K Genetic Diseases, Inborn %K Genetic Testing %K Genomics %K Humans %K Incidental Findings %K Infant %K Infant, Newborn %K Male %K Molecular Diagnostic Techniques %K Mutation %K Phenotype %K Referral and Consultation %K Sequence Analysis, DNA %X

IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.

OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.

DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.

RESULTS: A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.

CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

%B JAMA %V 312 %P 1870-9 %8 2014 Nov 12 %G eng %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/25326635?dopt=Abstract %R 10.1001/jama.2014.14601 %0 Journal Article %J BMC Med Genet %D 2013 %T Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology. %A Craigen, William J %A Graham, Brett H %A Wong, Lee-Jun %A Scaglia, Fernando %A Lewis, Richard Alan %A Bonnen, Penelope E %K Adult %K Computational Biology %K DNA Helicases %K Exome %K Genetic Diseases, X-Linked %K Genetic Loci %K Homozygote %K Humans %K Male %K Mitochondrial Diseases %K Multifunctional Enzymes %K Mutation, Missense %K Nephrolithiasis %K Oculocerebrorenal Syndrome %K Pedigree %K Phenotype %K Phosphoric Monoester Hydrolases %K RNA Helicases %K RNA, Ribosomal, 16S %K Sequence Analysis, DNA %K Spinocerebellar Ataxias %K Spinocerebellar Degenerations %X

BACKGROUND: The clinical features of mitochondrial disease are complex and highly variable, leading to challenges in establishing a specific diagnosis. Despite being one of the most commonly occurring inherited genetic diseases with an incidence of 1/5000, ~90% of these complex patients remain without a DNA-based diagnosis. We report our efforts to identify the pathogenetic cause for a patient with typical features of mitochondrial disease including infantile cataracts, CPEO, ptosis, progressive distal muscle weakness, and ataxia who carried a diagnosis of mitochondrial disease for over a decade.

METHODS: Whole exome sequencing and bioinformatic analysis of these data were conducted on the proband.

RESULTS: Exome sequencing studies showed a homozygous splice site mutation in SETX, which is known to cause Spinocerebellar Ataxia, Autosomal Recessive 1 (SCAR1). Additionally a missense mutation was identified in a highly conserved position of the OCRL gene, which causes Lowe Syndrome and Dent Disease 2.

CONCLUSIONS: This patient's complex phenotype reflects a complex genetic etiology in which no single gene explained the complete clinical presentation. These genetic studies reveal that this patient does not have mitochondrial disease but rather a genocopy caused by more than one mutant locus. This study demonstrates the benefit of exome sequencing in providing molecular diagnosis to individuals with complex clinical presentations.

%B BMC Med Genet %V 14 %P 83 %8 2013 Aug 16 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/23947751?dopt=Abstract %R 10.1186/1471-2350-14-83 %0 Journal Article %J Am J Hum Genet %D 2013 %T Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. %A Bonnen, Penelope E %A Yarham, John W %A Besse, Arnaud %A Wu, Ping %A Faqeih, Eissa A %A Al-Asmari, Ali Mohammad %A Saleh, Mohammad A M %A Eyaid, Wafaa %A Hadeel, Alrukban %A He, Langping %A Smith, Frances %A Yau, Shu %A Simcox, Eve M %A Miwa, Satomi %A Donti, Taraka %A Abu-Amero, Khaled K %A Wong, Lee-Jun %A Craigen, William J %A Graham, Brett H %A Scott, Kenneth L %A McFarland, Robert %A Taylor, Robert W %K Acidosis, Lactic %K Base Sequence %K Child %K Child, Preschool %K Chromosome Segregation %K DNA, Mitochondrial %K Electron Transport %K F-Box Proteins %K Female %K Fibroblasts %K Gene Dosage %K Genes, Recessive %K Genetic Predisposition to Disease %K Humans %K Infant %K Infant, Newborn %K Male %K Mitochondrial Encephalomyopathies %K Molecular Sequence Data %K Muscle, Skeletal %K Mutation %K Oxidative Phosphorylation %K Pedigree %K Protein Transport %K Ubiquitin-Protein Ligases %X

Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.

%B Am J Hum Genet %V 93 %P 471-81 %8 2013 Sep 05 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/23993193?dopt=Abstract %R 10.1016/j.ajhg.2013.07.017 %0 Journal Article %J Am J Hum Genet %D 2006 %T Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. %A Lalani, Seema R %A Safiullah, Arsalan M %A Fernbach, Susan D %A Harutyunyan, Karine G %A Thaller, Christina %A Peterson, Leif E %A McPherson, John D %A Gibbs, Richard A %A White, Lisa D %A Hefner, Margaret %A Davenport, Sandra L H %A Graham, John M %A Bacino, Carlos A %A Glass, Nancy L %A Towbin, Jeffrey A %A Craigen, William J %A Neish, Steven R %A Lin, Angela E %A Belmont, John W %K Abnormalities, Multiple %K Adolescent %K Animals %K Child %K Child, Preschool %K Coloboma %K DNA Helicases %K DNA Mutational Analysis %K DNA-Binding Proteins %K Embryo, Mammalian %K Facial Asymmetry %K Female %K Genotype %K Heart Defects, Congenital %K Humans %K In Situ Hybridization, Fluorescence %K Male %K Mice %K Molecular Sequence Data %K Mutation %K Pedigree %K Phenotype %K RNA Splice Sites %K RNA, Messenger %K Syndrome %X

CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.

%B Am J Hum Genet %V 78 %P 303-14 %8 2006 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16400610?dopt=Abstract %R 10.1086/500273