@article {684, title = {The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 02}, pages = {427-431}, abstract = {

PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

METHODS: Exome sequencing from 39 trios were analyzed.

RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

}, keywords = {Adult, Cell Cycle Proteins, Cerebrovascular Disorders, Child, Child, Preschool, Developmental Disabilities, DNA Helicases, Exome, Female, Genetic Predisposition to Disease, Humans, Intellectual Disability, Male, Methyltransferases, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Middle Aged, Moyamoya Disease, Mutation, Nuclear Proteins, Transcription Factors, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0639-2}, author = {Pinard, Amelie and Guey, St{\'e}phanie and Guo, Dongchuan and Cecchi, Alana C and Kharas, Natasha and Wallace, Stephanie and Regalado, Ellen S and Hostetler, Ellen M and Sharrief, Anjail Z and Bergametti, Fran{\c c}oise and Kossorotoff, Manoelle and Herv{\'e}, Dominique and Kraemer, Markus and Bamshad, Michael J and Nickerson, Deborah A and Smith, Edward R and Tournier-Lasserve, Elisabeth and Milewicz, Dianna M} } @article {363, title = {International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 May 04}, pages = {695-705}, abstract = {

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50\%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

}, keywords = {Databases, Factual, Exome, Genome, Human, Humans, International Cooperation, Rare Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.04.003}, author = {Boycott, Kym M and Rath, Ana and Chong, Jessica X and Hartley, Taila and Alkuraya, Fowzan S and Baynam, Gareth and Brookes, Anthony J and Brudno, Michael and Carracedo, Angel and den Dunnen, Johan T and Dyke, Stephanie O M and Estivill, Xavier and Goldblatt, Jack and Gonthier, Catherine and Groft, Stephen C and Gut, Ivo and Hamosh, Ada and Hieter, Philip and H{\"o}hn, Sophie and Hurles, Matthew E and Kaufmann, Petra and Knoppers, Bartha M and Krischer, Jeffrey P and Macek, Milan and Matthijs, Gert and Olry, Annie and Parker, Samantha and Paschall, Justin and Philippakis, Anthony A and Rehm, Heidi L and Robinson, Peter N and Sham, Pak-Chung and Stefanov, Rumen and Taruscio, Domenica and Unni, Divya and Vanstone, Megan R and Zhang, Feng and Brunner, Han and Bamshad, Michael J and Lochm{\"u}ller, Hanns} } @article {340, title = {Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {21-30}, abstract = {

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

}, keywords = {Adolescent, Adult, Bone and Bones, Brachydactyly, Cell Cycle Checkpoints, Exome, Female, Fibromuscular Dysplasia, Genes, Recessive, Heterozygote, Homozygote, Humans, Learning Disorders, Male, Middle Aged, Muscle, Smooth, Vascular, Mutation, Nuclear Proteins, Pedigree, Syndactyly, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.008}, author = {Guo, Dong-Chuan and Duan, Xue-Yan and Regalado, Ellen S and Mellor-Crummey, Lauren and Kwartler, Callie S and Kim, Dong and Lieberman, Kenneth and de Vries, Bert B A and Pfundt, Rolph and Schinzel, Albert and Kotzot, Dieter and Shen, Xuetong and Yang, Min-Lee and Bamshad, Michael J and Nickerson, Deborah A and Gornik, Heather L and Ganesh, Santhi K and Braverman, Alan C and Grange, Dorothy K and Milewicz, Dianna M} } @article {389, title = {MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Sep}, pages = {2415-2421}, abstract = {

Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80-85\% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.

}, keywords = {Adult, Base Sequence, Child, Child, Preschool, Exome, Female, Genes, Recessive, Humans, Male, Mutation, Missense, Nucleotidases, Osteochondrodysplasias, Pedigree, Radiography}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38349}, author = {Balasubramanian, Karthika and Li, Bing and Krakow, Deborah and Nevarez, Lisette and Ho, Patric J and Ainsworth, Julia A and Nickerson, Deborah A and Bamshad, Michael J and Immken, LaDonna and Lachman, Ralph S and Cohn, Daniel H} } @article {392, title = {Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Jul 06}, pages = {23-36}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1\% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

}, keywords = {Abnormalities, Multiple, Animals, Armadillo Domain Proteins, Basal Bodies, Base Sequence, Brain, Cerebellum, Cilia, Ciliopathies, Diagnostic Imaging, Exome, Eye Abnormalities, Genetic Predisposition to Disease, Humans, Kidney Diseases, Cystic, Mutation, Phenotype, Retina, Sequence Analysis, DNA, Up-Regulation, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.010}, author = {Van De Weghe, Julie C and Rusterholz, Tamara D S and Latour, Brooke and Grout, Megan E and Aldinger, Kimberly A and Shaheen, Ranad and Dempsey, Jennifer C and Maddirevula, Sateesh and Cheng, Yong-Han H and Phelps, Ian G and Gesemann, Matthias and Goel, Himanshu and Birk, Ohad S and Alanzi, Talal and Rawashdeh, Rifaat and Khan, Arif O and Bamshad, Michael J and Nickerson, Deborah A and Neuhauss, Stephan C F and Dobyns, William B and Alkuraya, Fowzan S and Roepman, Ronald and Bachmann-Gagescu, Ruxandra and Doherty, Dan} } @article {632, title = {Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.}, journal = {Int J Dermatol}, volume = {56}, year = {2017}, month = {2017 Dec}, pages = {1406-1413}, abstract = {

BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study.

METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families.

RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718~+~2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes.

CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

}, keywords = {1-Acylglycerol-3-Phosphate O-Acyltransferase, Aldehyde Oxidoreductases, Blister, Collagen Type VII, Consanguinity, DNA Mutational Analysis, DNA-Binding Proteins, Endonucleases, Epidermolysis Bullosa, Epidermolysis Bullosa Dystrophica, Epidermolysis Bullosa Simplex, Exome, Female, Flavoproteins, Homozygote, Humans, Ichthyosiform Erythroderma, Congenital, Ichthyosis Vulgaris, Ichthyosis, Lamellar, INDEL Mutation, Intermediate Filament Proteins, Keratin-14, Lipid Metabolism, Inborn Errors, Lipoxygenase, Male, Membrane Proteins, Mitochondrial Proteins, Muscular Diseases, Neoplasm Proteins, Nuclear Proteins, Pedigree, Periodontal Diseases, Phenotype, Photosensitivity Disorders, Porphyria, Variegate, Protoporphyrinogen Oxidase, Rare Diseases, Sjogren-Larsson Syndrome, Skin Diseases, Genetic, Transcription Factors, Xeroderma Pigmentosum}, issn = {1365-4632}, doi = {10.1111/ijd.13778}, author = {Shah, Khadim and Mehmood, Sabba and Jan, Abid and Abbe, Izoduwa and Hussain Ali, Raja and Khan, Anwar and Chishti, Muhammad S and Lee, Kwanghyuk and Ahmad, Farooq and Ansar, Muhammad and Shahzad, Shaheen and Nickerson, Deborah A and Bamshad, Michael J and Coucke, Paul J and Santos-Cortez, Regie L P and Spritz, Richard A and Leal, Suzanne M and Ahmad, Wasim} } @article {356, title = {Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, volume = {174}, year = {2017}, month = {2017 Jun}, pages = {381-389}, abstract = {

Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5\% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8\%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. {\textcopyright} 2017 Wiley Periodicals, Inc.

}, keywords = {Adult, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Biomarkers, Child, Exome, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Missense, Phenotype}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32527}, author = {Kim, Daniel Seung and Burt, Amber A and Ranchalis, Jane E and Wilmot, Beth and Smith, Joshua D and Patterson, Karynne E and Coe, Bradley P and Li, Yatong K and Bamshad, Michael J and Nikolas, Molly and Eichler, Evan E and Swanson, James M and Nigg, Joel T and Nickerson, Deborah A and Jarvik, Gail P} } @article {89, title = {Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {331-8}, abstract = {

The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among \~{}120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were~observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2.

}, keywords = {Amino Acid Sequence, Asian Continental Ancestry Group, Chromosomes, Human, Pair 19, Exome, Genes, Recessive, Hearing Loss, Humans, Lod Score, Logistic Models, Lysophospholipids, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Receptors, Lysosphingolipid, Sphingosine}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.004}, author = {Santos-Cortez, Regie Lyn P and Faridi, Rabia and Rehman, Atteeq U and Lee, Kwanghyuk and Ansar, Muhammad and Wang, Xin and Morell, Robert J and Isaacson, Rivka and Belyantseva, Inna A and Dai, Hang and Acharya, Anushree and Qaiser, Tanveer A and Muhammad, Dost and Ali, Rana Amjad and Shams, Sulaiman and Hassan, Muhammad Jawad and Shahzad, Shaheen and Raza, Syed Irfan and Bashir, Zil-E-Huma and Smith, Joshua D and Nickerson, Deborah A and Bamshad, Michael J and Riazuddin, Sheikh and Ahmad, Wasim and Friedman, Thomas B and Leal, Suzanne M} } @article {83, title = {Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP.}, journal = {BMC Med Genet}, volume = {17}, year = {2016}, month = {2016 Feb 16}, pages = {13}, abstract = {

BACKGROUND: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity.

METHODS: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression.

RESULTS: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old.

CONCLUSION: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Alleles, Asian Continental Ancestry Group, Child, Cloning, Molecular, Exome, Female, Genetic Linkage, Haplotypes, HEK293 Cells, Homozygote, Humans, Introns, Male, Mitral Valve Insufficiency, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA Splicing, Sequence Analysis, DNA, Trichothiodystrophy Syndromes, Young Adult}, issn = {1471-2350}, doi = {10.1186/s12881-016-0275-5}, author = {Shah, Khadim and Ali, Raja Hussain and Ansar, Muhammad and Lee, Kwanghyuk and Chishti, Muhammad Salman and Abbe, Izoduwa and Li, Biao and Smith, Joshua D and Nickerson, Deborah A and Shendure, Jay and Coucke, Paul J and Steyaert, Wouter and Bamshad, Michael J and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Ahmad, Wasim} } @article {164, title = {Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 May 07}, pages = {841-9}, abstract = {

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

}, keywords = {Arthrogryposis, Cytoskeletal Proteins, Exome, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Mutation, Myosins, Osteogenesis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.04.004}, author = {Chong, Jessica X and Burrage, Lindsay C and Beck, Anita E and Marvin, Colby T and McMillin, Margaret J and Shively, Kathryn M and Harrell, Tanya M and Buckingham, Kati J and Bacino, Carlos A and Jain, Mahim and Alanay, Yasemin and Berry, Susan A and Carey, John C and Gibbs, Richard A and Lee, Brendan H and Krakow, Deborah and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {194, title = {De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Mar 05}, pages = {462-73}, abstract = {

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

}, keywords = {Arthrogryposis, Contracture, Craniofacial Dysostosis, Cytoskeletal Proteins, Exome, Extremities, Face, Female, Gene Frequency, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Infant, Male, Muscle Hypotonia, Mutation, Missense, Sodium Channels}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.003}, author = {Chong, Jessica X and McMillin, Margaret J and Shively, Kathryn M and Beck, Anita E and Marvin, Colby T and Armenteros, Jose R and Buckingham, Kati J and Nkinsi, Naomi T and Boyle, Evan A and Berry, Margaret N and Bocian, Maureen and Foulds, Nicola and Uzielli, Maria Luisa Giovannucci and Haldeman-Englert, Chad and Hennekam, Raoul C M and Kaplan, Paige and Kline, Antonie D and Mercer, Catherine L and Nowaczyk, Malgorzata J M and Klein Wassink-Ruiter, Jolien S and McPherson, Elizabeth W and Moreno, Regina A and Scheuerle, Angela E and Shashi, Vandana and Stevens, Cathy A and Carey, John C and Monteil, Arnaud and Lory, Philippe and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {134, title = {Expanding the Molecular and Clinical Phenotype of SSR4-CDG.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Nov}, pages = {1048-51}, abstract = {

Congenital disorders of glycosylation (CDG) are a group of mostly autosomal recessive disorders primarily characterized by neurological abnormalities. Recently, we described a single CDG patient with a de novo mutation in the X-linked gene, Signal Sequence Receptor 4 (SSR4). We performed whole-exome sequencing to identify causal variants in several affected individuals who had either an undifferentiated neurological disorder or unsolved CDG of unknown etiology based on abnormal transferrin glycosylation. We now report eight affected males with either de novo (4) or inherited (4) loss of function mutations in SSR4. Western blot analysis revealed that the mutations caused a complete loss of SSR4 protein. In nearly all cases, the abnormal glycosylation of serum transferrin was only slightly above the accepted normal cutoff range.

}, keywords = {Calcium-Binding Proteins, Congenital Disorders of Glycosylation, DNA Mutational Analysis, Exome, Gene Order, Genes, X-Linked, Genetic Loci, Humans, Male, Membrane Glycoproteins, Mutation, Phenotype, Receptors, Cytoplasmic and Nuclear, Receptors, Peptide}, issn = {1098-1004}, doi = {10.1002/humu.22856}, author = {Ng, Bobby G and Raymond, Kimiyo and Kircher, Martin and Buckingham, Kati J and Wood, Tim and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Wong, Jonathan T S and Monteiro, Fabiola Paoli and Graham, Brett H and Jackson, Sheryl and Sparkes, Rebecca and Scheuerle, Angela E and Cathey, Sara and Kok, Fernando and Gibson, James B and Freeze, Hudson H} } @article {157, title = {Mutation of ATF6 causes autosomal recessive achromatopsia.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Sep}, pages = {941-50}, abstract = {

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.

}, keywords = {Activating Transcription Factor 6, Adolescent, Animals, Asian Continental Ancestry Group, Color Vision Defects, Consanguinity, DNA Mutational Analysis, Exome, Female, Frameshift Mutation, Genotyping Techniques, Homozygote, Humans, Limit of Detection, Male, Mice, Mice, Inbred C57BL, Pakistan, Pedigree, Phenotype, Retina, Signal Transduction}, issn = {1432-1203}, doi = {10.1007/s00439-015-1571-4}, author = {Ansar, Muhammad and Santos-Cortez, Regie Lyn P and Saqib, Muhammad Arif Nadeem and Zulfiqar, Fareeha and Lee, Kwanghyuk and Ashraf, Naeem Mahmood and Ullah, Ehsan and Wang, Xin and Sajid, Sundus and Khan, Falak Sher and Amin-ud-Din, Muhammad and Smith, Joshua D and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hameed, Abdul and Riazuddin, Saima and Ahmed, Zubair M and Ahmad, Wasim and Leal, Suzanne M} } @article {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {238, title = {Attitudes of genetics professionals toward the return of incidental results from exome and whole-genome sequencing.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {77-84}, abstract = {

Professional recommendations for the return of results from exome and whole-genome sequencing (ES/WGS) have been controversial. The lack of clear guidance about whether and, if so, how to return ES/WGS incidental results limits the extent to which individuals and families might benefit from ES/WGS. The perspectives of genetics professionals, particularly those at the forefront of using ES/WGS in clinics, are largely unknown. Data on stakeholder perspectives could help clarify how to weigh expert positions and recommendations. We conducted an online survey of 9,857 genetics professionals to learn their attitudes on the return of incidental results from ES/WGS and the recent American College of Medical Genetic and Genomics Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Of the 847 respondents, 760 completed the survey. The overwhelming majority of respondents thought that incidental ES/WGS results should be offered to adult patients (85\%), healthy adults (75\%), and the parents of a child with a medical condition (74\%). The majority thought that incidental results about adult-onset conditions (62\%) and carrier status (62\%) should be offered to the parents of a child with a medical condition. About half thought that offered results should not be limited to those deemed clinically actionable. The vast majority (81\%) thought that individual preferences should guide return. Genetics professionals{\textquoteright} perspectives on the return of ES/WGS results differed substantially from current recommendations, underscoring the need to establish clear purpose for recommendations on the return of incidental ES/WGS results as professional societies grapple with developing and updating recommendations.

}, keywords = {Adult, Attitude of Health Personnel, Child, Exome, Genetics, Medical, Genome, Human, Humans, Incidental Findings, Workforce}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.06.004}, author = {Yu, Joon-Ho and Harrell, Tanya M and Jamal, Seema M and Tabor, Holly K and Bamshad, Michael J} } @article {246, title = {Attitudes of non-African American focus group participants toward return of results from exome and whole genome sequencing.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2153-60}, abstract = {

Exome sequencing and whole genome sequencing (ES/WGS) present individuals with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, it is unclear which genetic results people want to receive (i.e., what type of genetic information they want to learn about themselves) or conversely not receive, and how they want to receive or manage results over time. Very little is known about whether and how attitudes toward receiving individual results from ES/WGS vary among racial/ethnic populations. We conducted 13 focus groups with a racially and ethnically diverse parent population (n = 76) to investigate attitudes toward return of individual results from WGS. We report on our findings for non-African American (non-AA) participants. Non-AA participants were primarily interested in genetic results on which they could act or "do something about." They defined "actionability" broadly to include individual medical treatment and disease prevention. The ability to plan for the future was both a motivation for and an expected benefit of receiving results. Their concerns focused on the meaning of results, specifically the potential inaccuracy and uncertainty of results. Non-AA participants expected healthcare providers to be involved in results management by helping them interpret results in the context of their own health and by providing counseling support. We compare and contrast these themes with those we previously reported from our analysis of African American (AA) perspectives to highlight the importance of varying preferences for results, characterize the central role of temporal orientation in framing expectations about the possibility of receiving ES/WGS results, and identify potential avenues by which genomic healthcare disparities may be inadvertently perpetuated.

}, keywords = {Adult, African Americans, Aged, Attitude to Health, Exome, Female, Focus Groups, Genome, Human, Humans, Male, Middle Aged, Sequence Analysis, DNA}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36610}, author = {Yu, Joon-Ho and Crouch, Julia and Jamal, Seema M and Bamshad, Michael J and Tabor, Holly K} } @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 {263, title = {Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.}, journal = {Am J Respir Crit Care Med}, volume = {189}, year = {2014}, month = {2014 Mar 15}, pages = {707-17}, abstract = {

RATIONALE: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.

OBJECTIVES: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.

METHODS: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.

MEASUREMENTS AND MAIN RESULTS: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85\% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 \% predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 {\textpm} Hz at 25{\textdegree}C), but an abnormal, circular beat pattern.

CONCLUSIONS: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

}, keywords = {Adolescent, Adult, Child, Cilia, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Female, Genetic Association Studies, Genetic Markers, Genetic Testing, Homozygote, Humans, Kartagener Syndrome, Linear Models, Male, Middle Aged, Mutation, Nasal Mucosa, Sequence Analysis, DNA, Young Adult}, issn = {1535-4970}, doi = {10.1164/rccm.201311-2047OC}, author = {Knowles, Michael R and Ostrowski, Lawrence E and Leigh, Margaret W and Sears, Patrick R and Davis, Stephanie D and Wolf, Whitney E and Hazucha, Milan J and Carson, Johnny L and Olivier, Kenneth N and Sagel, Scott D and Rosenfeld, Margaret and Ferkol, Thomas W and Dell, Sharon D and Milla, Carlos E and Randell, Scott H and Yin, Weining and Sannuti, Aruna and Metjian, Hilda M and Noone, Peadar G and Noone, Peter J and Olson, Christina A and Patrone, Michael V and Dang, Hong and Lee, Hye-Seung and Hurd, Toby W and Gee, Heon Yung and Otto, Edgar A and Halbritter, Jan and Kohl, Stefan and Kircher, Martin and Krischer, Jeffrey and Bamshad, Michael J and Nickerson, Deborah A and Hildebrandt, Friedhelm and Shendure, Jay and Zariwala, Maimoona A} } @article {265, title = {Solving glycosylation disorders: fundamental approaches reveal complicated pathways.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {161-75}, abstract = {

Over 100 human genetic disorders result from mutations in glycosylation-related genes. In 2013, a new glycosylation disorder was reported every 17 days. This trend will probably continue given that at least 2\% of the human genome encodes glycan-biosynthesis and -recognition proteins. Established biosynthetic pathways provide many candidate genes, but finding unanticipated mutated genes will offer new insights into glycosylation. Simple glycobiomarkers can be used in narrowing the candidates identified by exome and genome sequencing, and those can be validated by glycosylation analysis of serum or cells from affected individuals. Model organisms will expand the understanding of these mutations{\textquoteright} impact on glycosylation and pathology. Here, we highlight some recently discovered glycosylation disorders and the barriers, breakthroughs, and surprises they presented. We predict that some glycosylation disorders might occur with greater frequency than current estimates of their prevalence. Moreover, the prevalence of some disorders differs substantially between European and African Americans.

}, keywords = {Congenital Disorders of Glycosylation, Exome, Genome, Human, Glucose, Glycogen, Glycosylation, Homeostasis, Humans, Mannose, Mutation}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.10.024}, author = {Freeze, Hudson H and Chong, Jessica X and Bamshad, Michael J and Ng, Bobby G} } @article {303, title = {Attitudes of African Americans toward return of results from exome and whole genome sequencing.}, journal = {Am J Med Genet A}, volume = {161A}, year = {2013}, month = {2013 May}, pages = {1064-72}, abstract = {

Exome sequencing and whole genome sequencing (ES/WGS) present patients and research participants with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, this potential for benefit also risks disenfranchising populations such as African Americans (AAs) that are already underrepresented in genetic research and utilize genetic tests at lower rates than other populations. Understanding a diverse range of perspectives on consenting for ES/WGS and receiving ES/WGS results is necessary to ensure parity in genomic health care and research. We conducted a series of 13 focus groups (n = 76) to investigate if and how attitudes toward participation in ES/WGS research and return of results from ES/WGS differ between self-described AAs and non-AAs. The majority of both AAs and non-AAs were willing to participate in WGS studies and receive individual genetic results, but the fraction not interested in either was higher in AAs. This is due in part to different expectations of health benefits from ES/WGS and how results should be managed. Our results underscore the need to develop and test culturally tailored strategies for returning ES/WGS results to AAs.

}, keywords = {Adult, African Americans, Aged, Attitude, Exome, Female, Focus Groups, Genetic Research, Genome-Wide Association Study, Humans, Male, Middle Aged, Sequence Analysis, DNA, Surveys and Questionnaires, Washington}, issn = {1552-4833}, doi = {10.1002/ajmg.a.35914}, author = {Yu, Joon-Ho and Crouch, Julia and Jamal, Seema M and Tabor, Holly K and Bamshad, Michael J} } @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 {307, title = {Mutations in KCTD1 cause scalp-ear-nipple syndrome.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {621-6}, abstract = {

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Branchio-Oto-Renal Syndrome, Ear, External, Ectodermal Dysplasia, Exome, Female, Humans, Hypospadias, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Missense, Nipples, Pedigree, Phenotype, Protein Structure, Tertiary, Repressor Proteins, Scalp, Sequence Homology, Amino Acid}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.002}, author = {Marneros, Alexander G and Beck, Anita E and Turner, Emily H and McMillin, Margaret J and Edwards, Matthew J and Field, Michael and de Macena Sobreira, Nara Lygia and Perez, Ana Beatriz A and Fortes, Jose A R and Lampe, Anne K and Giovannucci Uzielli, Maria Luisa and Gordon, Christopher T and Plessis, Ghislaine and Le Merrer, Martine and Amiel, Jeanne and Reichenberger, Ernst and Shively, Kathryn M and Cerrato, Felecia and Labow, Brian I and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {304, title = {Practices and policies of clinical exome sequencing providers: analysis and implications.}, journal = {Am J Med Genet A}, volume = {161A}, year = {2013}, month = {2013 May}, pages = {935-50}, abstract = {

Exome and whole genome sequencing (ES/WGS) offer potential advantages over traditional approaches to diagnostic genetic testing. Consequently, use of ES/WGS in clinical settings is rapidly becoming commonplace. Yet there are myriad moral, ethical, and perhaps legal implications attached to the use of ES and health care professionals and institutions will need to consider these implications in the context of the varied practices and policies of ES service providers. We developed "core elements" of content and procedures for informed consent, data sharing, and results management and a quantitative scale to assess the extent to which research protocols met the standards established by these core elements. We then used these tools to evaluate the practices and policies of each of the 6 U.S. CLIA-certified labs offering clinical ES. Approaches toward informed consent, data sharing, and results return vary widely among ES providers as do the overall potential merits and disadvantages of each, and more importantly, the balance between the two.

}, keywords = {Exome, Humans, Information Dissemination, Informed Consent, Morals, Organizational Policy, Practice Patterns, Physicians{\textquoteright}, Sequence Analysis, DNA, United States}, issn = {1552-4833}, doi = {10.1002/ajmg.a.35942}, author = {Jamal, Seema M and Yu, Joon-Ho and Chong, Jessica X and Dent, Karin M and Conta, Jessie H and Tabor, Holly K and Bamshad, Michael J} } @article {294, title = {Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {398-404}, abstract = {

Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63\%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.

}, keywords = {Acute Disease, Adolescent, Adult, Amino Acid Sequence, Aneurysm, Dissecting, Aorta, Thoracic, Aortic Aneurysm, Thoracic, Cyclic GMP, Cyclic GMP-Dependent Protein Kinase Type I, Exome, Female, Fibroblasts, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Molecular Sequence Data, Muscle Contraction, Muscle, Smooth, Vascular, Mutation, Myosin Light Chains, Pedigree}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.06.019}, author = {Guo, Dong-Chuan and Regalado, Ellen and Casteel, Darren E and Santos-Cortez, Regie L and Gong, Limin and Kim, Jeong Joo and Dyack, Sarah and Horne, S Gabrielle and Chang, Guijuan and Jondeau, Guillaume and Boileau, Catherine and Coselli, Joseph S and Li, Zhenyu and Leal, Suzanne M and Shendure, Jay and Rieder, Mark J and Bamshad, Michael J and Nickerson, Deborah A and Kim, Choel and Milewicz, Dianna M} } @article {327, title = {Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.}, journal = {Am J Hum Genet}, volume = {90}, year = {2012}, month = {2012 May 04}, pages = {925-33}, abstract = {

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57\%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

}, keywords = {Adult, Child, Child, Preschool, Cohort Studies, Exome, Female, Haploinsufficiency, Humans, Limb Deformities, Congenital, Male, Mandibulofacial Dysostosis, Mutation, Reproducibility of Results, RNA Precursors, RNA Splicing Factors, RNA-Binding Proteins, Spliceosomes, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.04.004}, author = {Bernier, Francois P and Caluseriu, Oana and Ng, Sarah and Schwartzentruber, Jeremy and Buckingham, Kati J and Innes, A Micheil and Jabs, Ethylin Wang and Innis, Jeffrey W and Schuette, Jane L and Gorski, Jerome L and Byers, Peter H and Andelfinger, Gregor and Siu, Victoria and Lauzon, Julie and Fernandez, Bridget A and McMillin, Margaret and Scott, Richard H and Racher, Hilary and Majewski, Jacek and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Parboosingh, Jillian S} }