Search

Your search keyword '"Elmslie, F."' showing total 6 results
Start Over Author "Elmslie, F." Topic humans
6 results on '"Elmslie, F."'

1. Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders

Author

Evers, JMG, Laskowski, RA, Bertolli, M, Clayton-Smith, J, Deshpande, C, Eason, J, Elmslie, F, Flinter, F, Gardiner, C, Hurst, JA, Kingston, H, Kini, U, Lampe, AK, Lim, D, Male, A, Naik, S, Parker, MJ, Price, S, Robert, L, Sarkar, A, Straub, V, Woods, G, Thornton, JM, DDD Study, and Wright, CF

Subjects
0301 basic medicine, Male, DYRK1A, Protein Conformation, Developmental Disabilities, Mutation, Missense, Haploinsufficiency, Biology, Protein Serine-Threonine Kinases, medicine.disease_cause, DYRK1A Gene, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Autistic Disorder, Molecular Biology, Gene, Genetics (clinical), Mutation, General Medicine, Articles, Protein-Tyrosine Kinases, Phenotype, Pedigree, 030104 developmental biology, Protein kinase domain, Female, 030217 neurology & neurosurgery
Abstract

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein’s function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.

Published
2017

2. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D’Alessandro, M, Dabir, T, Davidson, R, Davies, S, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME

Subjects
Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

Published
2017

3. Delineation of the movement disorders associated with FOXG1 mutations

Author

Papandreou, A., Schneider, R. B., Augustine, E. F., Ng, J., Mankad, K., Meyer, E., Mctague, A., Ngoh, A., Hemingway, C., Robinson, Raoul, Varadkar, S. M., Kinali, M., Salpietro, V., O'Driscoll, M. C., Nigel Basheer, S., Webster, R. I., Mohammad, S. S., Pula, S., Mcgowan, M., Trump, N., Jenkins, L., Elmslie, F., Scott, R. H., Hurst, J. A., Perez-Duenas, B., Paciorkowski, A. R., and Kurian, M. A.

Subjects
Adult, Male, Movement Disorders, Adolescent, Infant, Forkhead Transcription Factors, Nerve Tissue Proteins, Article, Tertiary Care Centers, Young Adult, Phenotype, Child, Preschool, Mutation, Humans, Female, Child, Retrospective Studies
Abstract

Objective: The primary objective of this research was to characterize the movement disorders associated with FOXG1 mutations. Methods: We identified patients with FOXG1 mutations who were referred to either a tertiary movement disorder clinic or tertiary epilepsy service and retrospectively reviewed medical records, clinical investigations, neuroimaging, and available video footage. We administered a telephone-based questionnaire regarding the functional impact of the movement disorders and perceived efficacy of treatment to the caregivers of one cohort of participants. Results: We identified 28 patients with FOXG1 mutations, of whom 6 had previously unreported mutations. A wide variety of movement disorders were identified, with dystonia, choreoathetosis, and orolingual/facial dyskinesias most commonly present. Ninety-three percent of patients had a mixed movement disorder phenotype. In contrast to the phenotype classically described with FOXG1 mutations, 4 patients with missense mutations had a milder phenotype, with independent ambulation, spoken language, and normocephaly. Hyperkinetic involuntary movements were a major clinical feature in these patients. Of the symptomatic treatments targeted to control abnormal involuntary movements, most did not emerge as clearly beneficial, although 4 patients had a caregiver-reported response to levodopa. Conclusions: Abnormal involuntary movements are a major feature of FOXG1 mutations. Our study delineates the spectrum of movement disorders and confirms an expanding clinical phenotype. Symptomatic treatment may be considered for severe or disabling cases, although further research regarding potential treatment strategies is necessary.

Published
2016

4. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T.W., Gerety, S.S., Jones, W.D., van Kogelenberg, M., King, D.A., McRae, J., Morley, K.I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D.M., Bayzetinova, T., Clayton, S., Coomber, E.L., Gribble, S., Jones, P., Krishnappa, N., Mason, L.E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A.R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A.P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S.J., Bunyan, D.J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M.N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., D'Alessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, S.L.G., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S.A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D.J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., O'Shea, R., Ogilvie, C., Park, S., Parker, M.J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D.T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweier, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Shanrif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G.J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I.K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N.P., Parker, M., Firth, H.V., FitzPatrick, D.R., Wright, C.F., Barrett, J.C., Hurles, M.E., and The Deciphering Developmental Disorders Study, .

Subjects
Male, Parents, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Transposases, SYNGAP1, medicine.disease_cause, Bioinformatics, DEAD-box RNA Helicases, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, Missense mutation, Exome, Protein Phosphatase 2, Child, Dynamin I, Zebrafish, Exome sequencing, Genes, Dominant, Polycomb Repressive Complex 1, 0303 health sciences, Mutation, Multidisciplinary, Gene Expression Regulation, Developmental, Nuclear Proteins, DNA-Binding Proteins, Child, Preschool, Female, Adolescent, Mutation, Missense, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, 030304 developmental biology, Chromosome Aberrations, Homeodomain Proteins, Genome, Human, Mechanism (biology), Infant, Newborn, Infant, Phosphoproteins, United Kingdom, Human genetics, Repressor Proteins, Human genome, Carrier Proteins, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Published
2015

5. Linkage analysis of juvenile myoclonic epilepsy and microsatellite loci spanning 61 cM of human chromosome 6p in 19 nuclear pedigrees provides no evidence for a susceptibility locus in this region

Author

Elmslie, F. V., Williamson, M. P., Rees, M., Kerr, M., Kjeldsen, M. J., Pang, K. A., Sundqvist, A., Friis, M. L., Richens, A., Chadwick, D., Whitehouse, W. P., and Gardiner, R. M.

Subjects
Adult, Male, Adolescent, Models, Genetic, Genetic Linkage, Chromosome Mapping, Epilepsies, Myoclonic, Pedigree, Humans, Chromosomes, Human, Pair 6, Computer Simulation, Female, Lod Score, Child, Research Article, Microsatellite Repeats
Abstract

Linkage analysis in separately ascertained families of probands with juvenile myoclonic epilepsy (JME) has previously provided evidence both for and against the existence of a locus (designated "EJM1"), on chromosome 6p, predisposing to a trait defined as either clinical JME, its associated electroencephalographic abnormality, or idiopathic generalized epilepsy. Linkage analysis was performed in 19 families in which a proband and at least one first- or two second-degree relatives have clinical JME. Family members were typed for seven highly polymorphic microsatellite markers on chromosome 6p: D6S260, D6S276, D6S291, D6S271, D6S465, D6S257, and D6S254. Pairwise and multipoint linkage analysis was carried out under the assumptions of autosomal dominant inheritance at 70% and 50% penetrance and autosomal recessive inheritance at 70% and 50% penetrance. No significant evidence in favor of linkage to the clinical trait of JME was obtained for any locus. The region formally excluded (LOD score < -2) by using multipoint analysis varies depending on the assumptions made concerning inheritance parameters and the proportion of linked families, alpha-that is, the degree of locus heterogeneity. Further analysis either classifying all unaffected individuals as unknown or excluding a subset of four families in which pyknoleptic absence seizures were present in one or more individuals did not alter these conclusions.

Published
1996

6. Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum

Author

Calvin Soh, Sophie Calvert, Ram L. Kumar, Isabelle Desguerre, Kevin Talbot, Evangeline Wassmer, Axel Panzer, Andrea Berger, Anna de Burca, Anu Jacob, Andrea Whitney, Andrew P. Badrock, Frances Gibbon, Shelley MacDonald, Rhys H. Thomas, Reza Maroofian, Heather Burnett, Elizabeth Jones, Thomas Blauwblomme, Francois V. Bolduc, Jamal Ghoumid, Mickaël Ferrand, Yanick J. Crow, Emma M. Jenkinson, Camilo Toro, Diana Chiang, Roseline Caumes, Gillian I. Rice, Gemma Fisher, Gopinath M. Subramanian, Edoardo Monfrini, Renaud Touraine, Hilde T. Hilmarsen, Sarju G. Mehta, Imelda Hughes, Sumit Parikh, Edward Blair, Mary O'Driscoll, Sarah Dyack, Himanshu Goel, Kristin W. Barañano, Prab Prabhakar, Luis Seabra, Roberta Battini, John H. Livingston, Russell P. Saneto, Richard J. Leventer, Katrin Õunap, Heather Marshall, Andy Cheuk Him Ng, Duccio Maria Cordelli, Natasha Demic, Daniela Neumann, Natalie Boddaert, Michael J. Noetzel, S. Richard Dunham, Ehsan Ghayoor Karimiani, Johannes A. Buckard, Frances Elmslie, Raymond T. O'Keefe, Chloe A Stutterd, Richard Sandford, Imke Metz, Francis Ramond, Liesbeth De Waele, Alessio Di Fonzo, Emma Wakeling, David B. Clifford, Crow Y.J., Marshall H., Rice G.I., Seabra L., Jenkinson E.M., Baranano K., Battini R., Berger A., Blair E., Blauwblomme T., Bolduc F., Boddaert N., Buckard J., Burnett H., Calvert S., Caumes R., Ng A.C.-H., Chiang D., Clifford D.B., Cordelli D.M., de Burca A., Demic N., Desguerre I., De Waele L., Di Fonzo A., Dunham S.R., Dyack S., Elmslie F., Ferrand M., Fisher G., Karimiani E.G., Ghoumid J., Gibbon F., Goel H., Hilmarsen H.T., Hughes I., Jacob A., Jones E.A., Kumar R., Leventer R.J., MacDonald S., Maroofian R., Mehta S.G., Metz I., Monfrini E., Neumann D., Noetzel M., O'Driscoll M., Ounap K., Panzer A., Parikh S., Prabhakar P., Ramond F., Sandford R., Saneto R., Soh C., Stutterd C.A., Subramanian G.M., Talbot K., Thomas R.H., Toro C., Touraine R., Wakeling E., Wassmer E., Whitney A., Livingston J.H., O'Keefe R.T., and Badrock A.P.

Subjects
Male, 0301 basic medicine, Proband, 030105 genetics & heredity, Gene mutation, ribosomopathy, Compound heterozygosity, Genetic analysis, Loss of heterozygosity, Leukoencephalopathy, Consanguinity, Leukoencephalopathies, Pathology, Molecular, Child, Zebrafish, Genetics (clinical), Genetics, Molecular pathology, C/D box snoRNA U8, coats plus, Labrune syndrome, leukoencephalopathy with calcifications and cysts, SNORD118, Calcinosis, Middle Aged, 3. Good health, Child, Preschool, Female, Adult, Heterozygote, Adolescent, coats plu, Biology, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, RNA, Small Nucleolar, Genetic Association Studies, Aged, leukoencephalopathy with calcifications and cyst, Infant, Newborn, Infant, medicine.disease, Disease Models, Animal, 030104 developmental biology
Abstract

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Published
2021

Catalog

Books, media, physical & digital resources
See catalog results