Objective Riboflavin transporter deficiencies (RTDs), involving SLC52A3 and SLC52A2 genes, have recently been related to Brown-Vialetto-Van Laere (BVVL) syndrome, a hereditary paediatric condition associating motor neuropathy (MN) and deafness. BVVL/RTD has rarely been reported in adult patients, but is probably underdiagnosed due to poor knowledge and lack of awareness of this form of disease among neurologists. In this study, we aimed to investigate the phenotype and prognosis of RTD patients with late-onset MN. Methods We retrospectively collected clinical, biological and electrophysiological data from all French RTD patients with MN onset after 10 years of age (n=6) and extracted data from 19 other similar RTD patients from the literature. Results Adult RTD patients with MN had heterogeneous clinical presentations, potentially mimicking amyotrophic lateral sclerosis or distal hereditary motor neuropathy (56%), multinevritis with cranial nerve involvement (16%), Guillain-Barré syndrome (8%) and mixed motor and sensory neuronopathy syndromes (20%, only in SLC52A2 patients). Deafness was often diagnosed before MN (in 44%), but in some patients, onset began only with MN (16%). The pattern of weakness varied widely, and the classic pontobulbar palsy described in BVVL was not constant. Biochemical tests were often normal. The majority of patients improved under riboflavin supplementation (86%). Interpretation Whereas late-onset RTD may mimic different acquired or genetic causes of motor neuropathies, it is a diagnosis not to be missed since high-dose riboflavin per oral supplementation is often highly efficient.
We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome. We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome. Transcription factor II D (TFIID) consists of TATA binding protein (TBP) and 12–14 TBP-associated factors (TAFs). TFIID promotes transcriptional initiation by recognizing promoter DNA and facilitating the nucleation of other general transcription factors for assembly into a functional pre-initiation complex,1Papai G. Weil P.A. Schultz P. New insights into the function of transcription factor TFIID from recent structural studies.Curr. Opin. Genet. Dev. 2011; 21: 219-224Crossref PubMed Scopus (57) Google Scholar, 2Cianfrocco M.A. Kassavetis G.A. Grob P. Fang J. Juven-Gershon T. Kadonaga J.T. Nogales E. Human TFIID binds to core promoter DNA in a reorganized structural state.Cell. 2013; 152: 120-131Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 3Kotani T. Miyake T. Tsukihashi Y. Hinnebusch A.G. Nakatani Y. Kawaichi M. Kokubo T. Identification of highly conserved amino-terminal segments of dTAFII230 and yTAFII145 that are functionally interchangeable for inhibiting TBP-DNA interactions in vitro and in promoting yeast cell growth in vivo.J. Biol. Chem. 1998; 273: 32254-32264Crossref PubMed Scopus (46) Google Scholar, 4Bhattacharya S. Lou X. Hwang P. Rajashankar K.R. Wang X. Gustafsson J.A. Fletterick R.J. Jacobson R.H. Webb P. Structural and functional insight into TAF1-TAF7, a subcomplex of transcription factor II D.Proc. Natl. Acad. Sci. USA. 2014; 111: 9103-9108Crossref PubMed Scopus (28) Google Scholar, 5Bieniossek C. Papai G. Schaffitzel C. Garzoni F. Chaillet M. Scheer E. Papadopoulos P. Tora L. Schultz P. Berger I. The architecture of human general transcription factor TFIID core complex.Nature. 2013; 493: 699-702Crossref PubMed Scopus (111) Google Scholar and it also functions as a co-activator by interacting with transcriptional activators.1Papai G. Weil P.A. Schultz P. New insights into the function of transcription factor TFIID from recent structural studies.Curr. Opin. Genet. Dev. 2011; 21: 219-224Crossref PubMed Scopus (57) Google Scholar Subunits of TFIID have been suggested to play a possible role in neurodegenerative diseases and developmental delay when they are disrupted.6Herzfeld T. Nolte D. Grznarova M. Hofmann A. Schultze J.L. Müller U. X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism.Hum. Mol. Genet. 2013; 22: 941-951Crossref PubMed Scopus (27) Google Scholar, 7Jambaldorj J. Makino S. Munkhbat B. Tamiya G. Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice.Biochem. Biophys. Res. Commun. 2012; 425: 273-277Crossref PubMed Scopus (16) Google Scholar, 8Makino S. Kaji R. Ando S. Tomizawa M. Yasuno K. Goto S. Matsumoto S. Tabuena M.D. Maranon E. Dantes M. et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am. J. Hum. Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 9Sako W. Morigaki R. Kaji R. Tooyama I. Okita S. Kitazato K. Nagahiro S. Graybiel A.M. Goto S. Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia.Neuroscience. 2011; 189: 100-107Crossref PubMed Scopus (28) Google Scholar, 10Rooms L. Reyniers E. Scheers S. van Luijk R. Wauters J. Van Aerschot L. Callaerts-Vegh Z. D’Hooge R. Mengus G. Davidson I. et al.TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions.Eur. J. Hum. Genet. 2006; 14: 1090-1096Crossref PubMed Scopus (36) Google Scholar, 11Hellman-Aharony S. Smirin-Yosef P. Halevy A. Pasmanik-Chor M. Yeheskel A. Har-Zahav A. Maya I. Straussberg R. Dahary D. Haviv A. et al.Microcephaly thin corpus callosum intellectual disability syndrome caused by mutated TAF2.Pediatr. Neurol. 2013; 49: 411-416.e1Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 12Najmabadi H. Hu H. Garshasbi M. Zemojtel T. Abedini S.S. Chen W. Hosseini M. Behjati F. Haas S. Jamali P. et al.Deep sequencing reveals 50 novel genes for recessive cognitive disorders.Nature. 2011; 478: 57-63Crossref PubMed Scopus (689) Google Scholar Indeed, variants in TAF2 (MIM: 604912) and TBP (MIM: 600075) have been implicated in intellectual disability (ID) and developmental delay with or without corpus callosum hypoplasia.10Rooms L. Reyniers E. Scheers S. van Luijk R. Wauters J. Van Aerschot L. Callaerts-Vegh Z. D’Hooge R. Mengus G. Davidson I. et al.TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions.Eur. J. Hum. Genet. 2006; 14: 1090-1096Crossref PubMed Scopus (36) Google Scholar, 11Hellman-Aharony S. Smirin-Yosef P. Halevy A. Pasmanik-Chor M. Yeheskel A. Har-Zahav A. Maya I. Straussberg R. Dahary D. Haviv A. et al.Microcephaly thin corpus callosum intellectual disability syndrome caused by mutated TAF2.Pediatr. Neurol. 2013; 49: 411-416.e1Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 13Abu-Amero K.K. Hellani A. Salih M.A. Al Hussain A. al Obailan M. Zidan G. Alorainy I.A. Bosley T.M. Ophthalmologic abnormalities in a de novo terminal 6q deletion.Ophthalmic Genet. 2010; 31: 1-11Crossref PubMed Scopus (13) Google Scholar Recent work toward understanding the molecular basis of Cornelia de Lange syndrome (CdLS [MIM: 122470, 300590, 300882, 614701, 610759]) has also suggested that mutations in TAF6 (MIM: 602955), encoding a component of TFIID, play an important role in the pathogenesis of this syndrome.14Yuan B. Pehlivan D. Karaca E. Patel N. Charng W.-L. Gambin T. Gonzaga-Jauregui C. Sutton V.R. Yesil G. Bozdogan S.T. et al.Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.J. Clin. Invest. 2015; 125: 636-651Crossref PubMed Scopus (113) Google Scholar CdLS is a phenotypically and genetically heterogeneous syndrome characterized by distinct facial features, hirsutism, developmental delay, ID, and limb abnormalities,15Deardorff M.A. Krantz I.D. NIPBL and SMC1L1 (now SCM1A) and the Cornelia de Lange Syndrome.in: Epstein C.J. Erickson R.P. Wynshao-Boris A. Inborn Errors of Development. Oxford University Press, 2008: 1020-1031Google Scholar and mutations in several different genes have been implicated in contributing to this heterogeneous clinical presentation.16Gil-Rodríguez M.C. Deardorff M.A. Ansari M. Tan C.A. Parenti I. Baquero-Montoya C. Ousager L.B. Puisac B. Hernández-Marcos M. Teresa-Rodrigo M.E. et al.De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.Hum. Mutat. 2015; 36: 454-462Crossref PubMed Scopus (55) Google Scholar, 17Izumi K. Nakato R. Zhang Z. Edmondson A.C. Noon S. Dulik M.C. Rajagopalan R. Venditti C.P. Gripp K. Samanich J. et al.Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin.Nat. Genet. 2015; 47: 338-344Crossref PubMed Scopus (83) Google Scholar, 18Kline A.D. Calof A.L. Schaaf C.A. Krantz I.D. Jyonouchi S. Yokomori K. Gauze M. Carrico C.S. Woodman J. Gerton J.L. et al.Cornelia de Lange syndrome: further delineation of phenotype, cohesin biology and educational focus, 5th Biennial Scientific and Educational Symposium abstracts.Am. J. Med. Genet. A. 2014; 164A: 1384-1393Crossref PubMed Scopus (5) Google Scholar, 19Mannini L. Cucco F. Quarantotti V. Krantz I.D. Musio A. Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.Hum. Mutat. 2013; 34: 1589-1596Crossref PubMed Scopus (129) Google Scholar Two mutations in TAF6 were implicated in disease pathogenesis in some individuals with phenotypic features of CdLS and were shown, through biochemical investigations, to reduce binding of TAF6 to other core components of TFIID.14Yuan B. Pehlivan D. Karaca E. Patel N. Charng W.-L. Gambin T. Gonzaga-Jauregui C. Sutton V.R. Yesil G. Bozdogan S.T. et al.Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.J. Clin. Invest. 2015; 125: 636-651Crossref PubMed Scopus (113) Google Scholar A recent paper nominated TAF1 (MIM: 313650) as a candidate gene for ID on the basis of segregation of missense variants in two different pedigrees; however, no clinical information other than ID was provided.20Hu H. Haas S.A. Chelly J. Van Esch H. Raynaud M. de Brouwer A.P. Weinert S. Froyen G. Frints S.G. Laumonnier F. et al.X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.Mol. Psychiatry. 2015; (Published online February 3, 2015)https://doi.org/10.1038/mp.2014.193Crossref Scopus (185) Google Scholar TAF1 encodes the largest subunit of the TFIID complex and has been ranked 53rd among the top 1,003 constrained human genes in a recent population-scale study,21Samocha K.E. Robinson E.B. Sanders S.J. Stevens C. Sabo A. McGrath L.M. Kosmicki J.A. Rehnström K. Mallick S. Kirby A. et al.A framework for the interpretation of de novo mutation in human disease.Nat. Genet. 2014; 46: 944-950Crossref PubMed Scopus (611) Google Scholar suggesting that TAF1 plays a critical role in normal cellular function. Previous work in Drosophila cells has shown that TAF1 depletion increases the magnitude of the initial transcription burst and causes delay in the shutoff of transcription upon removal of the stimulus.22Pennington K.L. Marr S.K. Chirn G.W. Marr 2nd, M.T. Holo-TFIID controls the magnitude of a transcription burst and fine-tuning of transcription.Proc. Natl. Acad. Sci. USA. 2013; 110: 7678-7683Crossref PubMed Scopus (17) Google Scholar The authors showed that the magnitude of the transcriptional response to the same signaling event, even at the same promoter, can vary greatly depending on the composition of the TFIID complex in the cell. In addition, and consistent with the notion that TAF1 is important in controlling the binding patterns of TFIID to specific promoter regions, this study showed that the set of genes conferring increased expression were enriched with TATA-containing promoters, suggesting an association between the depletion of TAF1 and increased expression of genes with the TATA motif. The genomic region containing TAF1 has also been suggested to play an important role in X-linked dystonia-parkinsonism (XDP [MIM: 314250]), although the exact mechanism remains undetermined6Herzfeld T. Nolte D. Grznarova M. Hofmann A. Schultze J.L. Müller U. X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism.Hum. Mol. Genet. 2013; 22: 941-951Crossref PubMed Scopus (27) Google Scholar, 8Makino S. Kaji R. Ando S. Tomizawa M. Yasuno K. Goto S. Matsumoto S. Tabuena M.D. Maranon E. Dantes M. et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am. J. Hum. Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 23Domingo A. Westenberger A. Lee L.V. Brænne I. Liu T. Vater I. Rosales R. Jamora R.D. Pasco P.M. Cutiongco-Dela Paz E.M. et al.New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3).Eur. J. Hum. Genet. 2015; 23: 1334-1340Crossref PubMed Scopus (59) Google Scholar (Dy et al., 2015, Movement Disorders, abstract). XDP is an X-linked recessive movement disorder characterized by adult-onset dystonia and parkinsonism, which lead to eventual death as a result of oropharyngeal dystonia or secondary infections.24Nolte D. Niemann S. Müller U. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc. Natl. Acad. Sci. USA. 2003; 100: 10347-10352Crossref PubMed Scopus (108) Google Scholar Studies investigating the molecular basis of XDP have demonstrated aberrant neuron-specific expression levels of TAF1 isoforms in neuronal tissue containing TAF1 variants. Herzfeld et al. corroborated previous reports suggesting that a reduction in TAF1 expression is associated with large-scale expression differences across hundreds of genes,6Herzfeld T. Nolte D. Grznarova M. Hofmann A. Schultze J.L. Müller U. X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism.Hum. Mol. Genet. 2013; 22: 941-951Crossref PubMed Scopus (27) Google Scholar and studies in rat and mouse brain have also corroborated the importance and relevance of TAF1 expression patterns specific to neuronal tissues.7Jambaldorj J. Makino S. Munkhbat B. Tamiya G. Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice.Biochem. Biophys. Res. Commun. 2012; 425: 273-277Crossref PubMed Scopus (16) Google Scholar, 9Sako W. Morigaki R. Kaji R. Tooyama I. Okita S. Kitazato K. Nagahiro S. Graybiel A.M. Goto S. Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia.Neuroscience. 2011; 189: 100-107Crossref PubMed Scopus (28) Google Scholar In this study, we describe a recognizable syndrome attributed to mutations in TAF1. This work represents a collaborative research effort between independent groups engaged in studying the molecular basis of human disease. A “genotype-first” approach25Stessman H.A. Bernier R. Eichler E.E. A genotype-first approach to defining the subtypes of a complex disease.Cell. 2014; 156: 872-877Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar was used for finding families with variants in TAF1. This approach included phenotypic evaluations and screening of families with individuals harboring mutations in TAF1. This process was facilitated by the use of databases such as DECIPHER and reporting initial findings on the BioRxiv preprint server.26O’Rawe, J., Wu, Y., Rope, A., Barrón, L.T.J., Swensen, J., Fang, H., Mittelman, D., Highnam, G., Robison, R., Yang, E., et al. (2015). A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features. bioRxiv, http://dx.doi.org/10.1101/014050.Google Scholar These efforts culminated in a study cohort of 14 affected individuals from 11 unrelated families. Twelve of these individuals (from nine unrelated families) contain single-nucleotide changes in TAF1, and two (from two unrelated families) have large duplications involving TAF1. Written informed consent was obtained from all study participants for all families, except in those instances when exomes were ordered through GeneDx on clinical grounds, and research was carried out in compliance with the Declaration of Helsinki. Shared phenotypic features representing the cardinal characteristcs of this syndrome (see Figures 1 and 2, Tables 1, 2, and S5, and Movies S1, S2, S3, S4, S5, S6, and S7) include global developmental delay, ID, characteristic facial dysmorphologies, and generalized hypotonia. Shared facial dysmorphologies include prominent supraorbital ridges, down-slanted palpebral fissures, sagging cheeks, a long philtrum, low-set and protruding ears, a long face, a high palate, a pointed chin, and anteverted nares. The probands also share a characteristic gluteal crease with a sacral caudal remnant (Figure S13), although spine MRI on two probands did not show any major underlying defect (Figure S8). The affected individuals have generalized hypotonia, as well as joint hypermobility. Other widely shared features include hearing impairment, microcephaly, and hypoplasia of the corpus callosum (Figure S7 and Table S5). Interestingly, probands 8A (II-1 in family 8; Figure 2) and 11A (II-1 in family 11; Figure 3) are also affected by abnormal development of the thoracic cage. Some additional neurological features include spastic diplegia, dystonic movements, and tremors. Individuals 8A, 10A (IV-3 in family 10; Figure 3), and 11A have progressive symptoms, and one individual (11A) died of severe cardiopulmonary insufficiency attributed to an infection. Importantly, probands bearing duplications of TAF1 (10A and 11A) not only demonstrate severe and progressive neurodegeneration but also do not share some of the more common features of the rest of the probands (see Table 1 and Figures 1 and 3 for comparison). Detailed clinical information is included in the Supplemental Note.Figure 2TAF1 Domains, Variant Scores, and ExAC Sequence Variation PlotShow full caption(A) Pedigree drawings of the nine families who were found to harbor TAF1 SNVs (NCBI Gene ID: 6872 according to the GRCh37.p13 assembly). Black dots indicate maternal carriers.(B) All nine SNVs are listed and annotated with CADD, SIFT, GERP++, and phyloP scores (which indicate conservation across 99 vertebrate genomes and humans). All of the SNVs are considered to be potentially deleterious by all of the listed annotations, except for c.3708A>G, which is a splice-site variant and as a consequence is not necessarily expected to be categorized as deleterious by any of the listed scores, because it does not affect amino acid composition of the predicted protein.(C) Known TAF1 domains are shown with respect to their corresponding genic positions. All but non-synonymous variants reported in the ExAC Browser for TAF1 are plotted below as lines; white and gray indicate exon boundaries. Red lines indicate the relative positions of the eight missense variants described in this paper (see Table 2). Numerals link the sequence variants shown on the ExAC plot to their familial origin, and those noted with a star fall within TAF1 regions that are significantly underrepresented by non-synonymous sequence variation in the ExAC Browser in European and Latin populations (p values of 0.032 and 0.037 for the first [c.2419T>C, c.2926G>C, and c.3736C>T] and second [c.3708A>G ] clusters, according to Cucala’s hypothesis-free multiple scan statistic with a variable window27Cucala L. A hypothesis-free multiple scan statistic with variable window.Biom. J. 2008; 50: 299-310Crossref PubMed Scopus (17) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Summary of the Clinical Features of TAF1 ID SyndromeFeatures (Human Phenotype Ontology Nos.)Proband1A1B2A3A4A5A6A7A8A8B8C9A10AaProbands containing duplications; they are generally less similar to the probands containing SNVs and share fewer common clinical features.11AaProbands containing duplications; they are generally less similar to the probands containing SNVs and share fewer common clinical features.SexMMMMMMMMMMMMMMAge (years)1513569322119413168Postnatal growth retardation (HP: 0008897)++++++−−++++UK+Delayed gross motor development (HP: 0002194)++++++++++++++Delayed speech and language development (HP: 0000750)+++++++++++UK++Oral-pharyngeal dysphagia (HP: 0200136)++++UK+UK−+++UK+UKProminent supraorbital ridges (HP: 0000336)++−+UK−+−++++++Downslanted palpebral fissures (HP: 0000494)+++−+++−+++−+UKSagging cheeks++−−−+−−++++++Long philtrum (HP: 0000343)++++++−+++++−−Low-set ears (HP: 0000369)+++++++−++++−+Protruding ears (HP: 0000411)+++++++−+++−−+Long face (HP: 0000276)++−−UK++−++++++High palate (HP: 0000218)UKUK++−++−++++++Pointed chin (HP: 0000307)++−−+++−+++−++Anteverted nares (HP: 0000463)−−++++−+++++−+Hearing impairment (HP: 0000365)++++UK+−−+++−UK−Chromic otitis media (HP: 0000389)+++−++−++++−UK−Strabismus (HP: 0000486)++++UK++−+−−++−Microcephaly (HP: 0000252)+++++−−+++++−−Hypoplasia of the corpus callosum (HP: 0002079)+++UK+++UK++++UK−Generalized hypotonia (HP: 0001290)+++++++−++++−+Unusual gluteal crease with sacral caudal remnant and sacral dimple (abnormal sacral segmentation [HP: 0008468] and prominent protruding coccyx [HP: 0008472])++++++++++++UK−Joint hypermobility (HP: 0001382)++−+UK+−−++++−UKAutistic behaviors (HP: 0000729)+++−UKUK+++++−++Intellectual disability (HP: 0001249)+++++UK++++++++This table demonstrates clinical features shared by eight or more probands across all affected individuals in the families. See Table S5 for a more comprehensive phenotypic table that includes phenotypic and clinical idiosyncrasies. Abbreviations are as follows: M, male; and UK, unknown.a Probands containing duplications; they are generally less similar to the probands containing SNVs and share fewer common clinical features. Open table in a new tab Table 2Summary of TAF1 Variants across All Affected Individuals in This StudyProbandInheritanceGenetic BackgroundTAF1 Mutation (hg19)1AmaternalEuropean decentchrX: g.70621541T>C (c.4010T>C; p.Ile1337Thr)1BmaternalEuropean decentchrX: g.70621541T>C (c.4010T>C; p.Ile1337Thr)2Ade novoEuropean decentchrX: g.70607243T>C (c.2419T>C; p.Cys807Arg)3Ade novoEuropean decentchrX: g.70618477C>T (c.3736C>T; p.Arg1246Trp)4Ade novoEuropean decentchrX: g.70601686T>A (c.1514T>A; p.Ile505Asn)5AmaternalEcuadorianchrX: g.70618449A>G (c.3708A>G; r.[3708a>g; 3681_3708del28]; p.Arg1228Ilefs∗16)6Ade novoEuropean decentchrX: g.70643003A>C (c.4549A>C; p.Asn1517His)7Ade novoBritishchrX: g.70627912G>A (c.4355G>A; p.Arg1431His)8AmaternalColombianchrX: g.70602671C>T (c.1786C>T; p.Pro596Ser)8BmaternalColombianchrX: g.70602671C>T (c.1786C>T; p.Pro596Ser)8CmaternalColombianchrX: g.70602671C>T (c.1786C>T; p.Pro596Ser)9Ade novoSpanishchrX: g.70612503G>C (c.2926G>C; p.Asp976His)10AmaternalAlbanian0.423 Mb duplication including TAF1 and other genes at Xq13.1(70,370,794–70,794,385); deletion containing KANSL1 and other genes at 17q21.31 (0.63 Mb)11Ade novoGreek0.42 Mb duplication including TAF1 and other genes: arr Xq13.1(70,287,519–70,711,110)×2 Open table in a new tab Figure 3Duplications Involving TAF1 from Families 10 and 11Show full caption(A) Pedigree drawings of families 10 and 11.(B) The facial phenotype of proband 10A is notable for prominent supraorbital ridges, down-slanted palpebral fissures, sagging cheeks, a long face, a high palate, and a pointed chin.(C) Chromosome X cytobands are plotted above a more focused view of the region containing duplications that involve TAF1 in families 10 and 11. UCSC refGenes (from the UCSC Genome Browser tables) whose canonical transcript start or stop sites overlap either of the two duplications are plotted.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Pedigree drawings of the nine families who were found to harbor TAF1 SNVs (NCBI Gene ID: 6872 according to the GRCh37.p13 assembly). Black dots indicate maternal carriers. (B) All nine SNVs are listed and annotated with CADD, SIFT, GERP++, and phyloP scores (which indicate conservation across 99 vertebrate genomes and humans). All of the SNVs are considered to be potentially deleterious by all of the listed annotations, except for c.3708A>G, which is a splice-site variant and as a consequence is not necessarily expected to be categorized as deleterious by any of the listed scores, because it does not affect amino acid composition of the predicted protein. (C) Known TAF1 domains are shown with respect to their corresponding genic positions. All but non-synonymous variants reported in the ExAC Browser for TAF1 are plotted below as lines; white and gray indicate exon boundaries. Red lines indicate the relative positions of the eight missense variants described in this paper (see Table 2). Numerals link the sequence variants shown on the ExAC plot to their familial origin, and those noted with a star fall within TAF1 regions that are significantly underrepresented by non-synonymous sequence variation in the ExAC Browser in European and Latin populations (p values of 0.032 and 0.037 for the first [c.2419T>C, c.2926G>C, and c.3736C>T] and second [c.3708A>G ] clusters, according to Cucala’s hypothesis-free multiple scan statistic with a variable window27Cucala L. A hypothesis-free multiple scan statistic with variable window.Biom. J. 2008; 50: 299-310Crossref PubMed Scopus (17) Google Scholar). This table demonstrates clinical features shared by eight or more probands across all affected individuals in the families. See Table S5 for a more comprehensive phenotypic table that includes phenotypic and clinical idiosyncrasies. Abbreviations are as follows: M, male; and UK, unknown. (A) Pedigree drawings of families 10 and 11. (B) The facial phenotype of proband 10A is notable for prominent supraorbital ridges, down-slanted palpebral fissures, sagging cheeks, a long face, a high palate, and a pointed chin. (C) Chromosome X cytobands are plotted above a more focused view of the region containing duplications that involve TAF1 in families 10 and 11. UCSC refGenes (from the UCSC Genome Browser tables) whose canonical transcript start or stop sites overlap either of the two duplications are plotted. Several strategies were used for identifying candidate disease-related sequence variation. These included whole-genome sequencing, exome sequencing, targeted gene-panel sequencing, and microarray-based strategies (Figures S1–S5 and Tables S1–S4). Sanger sequencing was used for validating sequence variations. Many of the families studied here underwent genotyping via clinical microarrays or gene-specific sequencing for a small number of genomic regions. See the Supplemental Data for more-detailed descriptions of the sequencing and analysis methods used for each family. All 14 affected individuals were found to contain TAF1 sequence variants, the majority of which (11 out of 14) are missense variants. One proband (II-1 in family 5; 5A in Figure 2) was found to have a variant that influences TAF1 splicing, and two probands (10A and 11A) were found to have a duplication that involves TAF1. As stated above, the two probands with duplications exhibit less overlap with those who harbor single-nucleotide changes (see Table 1) and exhibit severe progressive neurologic impairment. All of the mutations reported here, including the duplications, are de novo or co-segregate with the phenotype in other affected male individuals (see Figures 2 and 3). Families 1 and 10 were tested for X chromosome inactivation, which showed that female carriers of TAF1 mutations and duplications demonstrate highly skewed inactivation (99:1). The female carriers in families 5 and 11 were not informative for the polymorphic CAG repeat in the human androgen-receptor gene. All missense variants were found to affect evolutionarily conserved residues (Figure 2B) and were not present at any frequency in public databases such as dbSNP137, 1000 Genomes phase 1, the NHLBI Exome Sequencing Project Exome Variant Server (ESP6500), or ExAC Browser version 0.2, which contains allelic information derived from ∼60,000 exome sequences. The TAF1 missense variants were also predicted to be deleterious by a range of prediction software (CADD, SIFT, GERP++, and phyloP) (Figure 2B). The splice-site variant discovered in family 5 was not predicted to be deleterious by the prediction software listed. However, this variant does not change the amino acid content of the predicted protein; instead, it affects TAF1 splicing in both the mother and the proband (Figure S11). In addition, the single-nucleotide variants (SNVs) described here fall within TAF1 regions that are relat
Abstract Objective γ‐Aminobutyric acid (GABA) A ‐receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA A ‐receptor–related disorders as a whole and seek possible genotype–phenotype correlations. Methods We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA A ‐receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. Results We gathered the reported patients in three epileptic phenotypes: 15 patients with fever‐related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA A ‐receptor subunit gene, whereas N‐terminal variants seemed to be related to milder phenotypes. Significance GABA A ‐receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.
Summary: Purpose: Unverricht‐Lundborg disease (ULD) is the most frequent form of progressive myoclonus epilepsy. ULD is caused mostly by a homozygous expansion of a dodecamer repeat in the cystatin B gene ( CSTB ) promoter. We present here a clinical and molecular study of 14 ULD patients originating from Reunion Island, a French island in the Indian Ocean. Methods: These ULD patients were clinically evaluated, and the diagnosis of ULD was confirmed molecularly. We analyzed 12 microsatellites flanking CSTB and estimated the date of introduction of the ULD mutation on Reunion Island. Results: These cases were clinically very similar, with the typical myoclonus syndrome associated with generalized tonic–clonic seizures, cerebellar involvement and, in some cases, mild mental deterioration. The mean age at onset was 9.6 years (range, 5–14 years), and the mean disease duration was 27 years (range, 5–47 years). The 14 patients harbored the typical ULD mutation, with variable degrees of expansion (mean of 56.3 repeats; range, 49–63). A founder effect was detected, with all but one of the Reunion ULD chromosomes displaying expansions belonging to the same haplotype, 1‐1‐1‐2‐6‐4‐3. We estimated the date of arrival of the most recent common ancestor (MRCA) of these patients on Reunion Island to the middle of the eighteenth century. Conclusions: These Reunion ULD patients displayed a homogeneous phenotype. Our molecular results are compatible with the instability of the repeat expansion and revealed a founder effect in Reunion ULD patients and the existence of a MRCA about 12 generations ago.
Summary Objective Mutations in the syntaxin binding protein 1 gene ( STXBP 1 ) have been associated mostly with early onset epileptic encephalopathies ( EOEE s) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography ( EEG ) features associated with STXBP 1 ‐related epilepsies to orient molecular screening. Methods We screened STXBP 1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging ( MRI ) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP 1 found using array comparative genomic hybridization ( CGH ). Results We found a mutation of STXBP 1 in 22 patients and included 2 additional patients with a deletion including STXBP 1 . In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression‐burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. Significance Our data confirm that STXBP 1 mutations are associated with neonatal‐infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG , and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP 1 molecular screening.
Dans 20 a 40 % des cas, suivant les series, les enfants vus dans des centres specialises en epileptologie presentent des mouvement paroxystiques non epileptiques. Dans ce chapitre introductif, nous proposons une demarche diagnostique pour identifier les mouvements paroxystiques non epileptiques et les differencier des crises epileptiques, en les presentant en fonction de l’âge (nouveau-nes, nourrissons, enfants, adolescents) avec leurs principaux symptomes. Cette demarche clinique a pour but de permettre de demander avec discernement les examens complementaires pour affirmer le diagnostic, l’investigation essentielle dans les cas difficiles etant la video-EEG critique.
Movement Disorders Clinical Practice-is an online-only journal committed to publishing high quality peer reviewed articles related to clinical aspects of movement disorders which broadly include phenomenology (interesting case/case series/rarities), investigative (for e.g.genetics, imaging), translational (phenotype-genotype or other) and treatment aspects (clinical guidelines, diagnostic and treatment algorithms).In addition the journal will encourage the publication of educative material (solicited and unsolicited reviews), clinical-pathological cases, drug trials results and task force reports related to the field of movement disorders.MDCP encourages the submission of multimedia material accompanying all types of articles.
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