RESUMO
BACKGROUND: Intellectual disability syndromes (IDSs) with or without developmental delays affect up to 3% of the world population. We sought to clinically and genetically characterise a novel IDS segregating in five unrelated consanguineous families. METHODS: Clinical analyses were performed for eight patients with intellectual disability (ID). Whole-exome sequencing for selected participants followed by Sanger sequencing for all available family members was completed. Identity-by-descent (IBD) mapping was carried out for patients in two Egyptian families harbouring an identical variant. RNA was extracted from blood cells of Turkish participants, followed by cDNA synthesis and real-time PCR for TTC5. RESULTS: Phenotype comparisons of patients revealed shared clinical features of moderate-to-severe ID, corpus callosum agenesis, mild ventriculomegaly, simplified gyral pattern, cerebral atrophy, delayed motor and verbal milestones and hypotonia, presenting with an IDS. Four novel homozygous variants in TTC5: c.629A>G;p.(Tyr210Cys), c.692C>T;p.(Ala231Val), c.787C>T;p.(Arg263Ter) and c.1883C>T;p.(Arg395Ter) were identified in the eight patients from participating families. IBD mapping revealed that c.787C>T;p.(Arg263Ter) is a founder variant in Egypt. Missense variants c.629A>G;p.(Tyr210Cys) and c.692C>T;p.(Ala231Val) disrupt highly conserved residues of TTC5 within the fifth and sixth tetratricopeptide repeat motifs which are required for p300 interaction, while the nonsense variants are predicted to decrease TTC5 expression. Functional analysis of variant c.1883C>T;p.(Arg395Ter) showed reduced TTC5 transcript levels in accordance with nonsense-mediated decay. CONCLUSION: Combining our clinical and molecular data with a recent case report, we identify the core and variable clinical features associated with TTC5 loss-of-function variants and reveal the requirement for TTC5 in human brain development and health.
Assuntos
Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Alelos , Criança , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/patologia , Egito/epidemiologia , Exoma/genética , Feminino , Homozigoto , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Linhagem , Fenótipo , Sequenciamento do ExomaRESUMO
Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertionâdeletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.
Assuntos
Variações do Número de Cópias de DNA , Linhagem , Paraplegia Espástica Hereditária , Humanos , Masculino , Feminino , Paraplegia Espástica Hereditária/genética , Éxons/genética , Criança , Adolescente , Adulto , Sequenciamento do Exoma , Pré-Escolar , Complexo 4 de Proteínas Adaptadoras/genética , Consanguinidade , Homozigoto , Fenótipo , Adulto Jovem , ProteínasRESUMO
Neuromuscular disorders encompass a broad range of phenotypes and genetic causes. We investigated a consanguineous family in which multiple patients had a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy. Exome sequencing was completed on the DNA of three of the four patients. We identified a novel missense variant in DCAF13, ENST00000612750.5, NM_015420.7, c.907 G > A;p.(Asp303Asn), ENST00000616836.4, NM_015420.6, c.1363 G > A:p.(Asp455Asn) (rs1209794872) segregating with this phenotype; being homozygous in all four affected patients and heterozygous in the unaffected individuals. The variant was extremely rare in the public databases (gnomAD allele frequency 0.000007081); was absent from the DNA of 300 ethnically matched controls and affected an amino acid which has been conserved across 1-2 billion years of evolution in eukaryotes. DCAF13 contains three WD40 domains and is hypothesized to have roles in both rRNA processing and in ubiquitination of proteins. Analysis of DCAF13 with the p.(Asp455Asn) variant predicted that the amino acid change is deleterious and affects a ß-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Previously, a heterozygous variant of DCAF13 NM_015420.6, c.20 G > C:p.(Trp7Ser) with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder. Our study indicates a potential role of biallelic DCAF13 variants in neuromuscular disorders. Screening of additional patients with similar phenotype may broaden the allelic and phenotypic spectrum due to DCAF13 variants.
Assuntos
Transtorno do Espectro Autista , Epilepsia , Humanos , Homozigoto , Epilepsia/genética , Frequência do Gene , Mutação de Sentido Incorreto , Fenótipo , Linhagem , Proteínas de Ligação a RNA/genéticaRESUMO
PURPOSE: This study explores interactional dynamics and relational tensions within English NHS Foundation Trust board meetings that are influenced by governance structure and the board composition. DESIGN/METHODOLOGY/APPROACH: This paper draws upon an ethnonarrative approach to enable the understanding of the nuances of boardroom interactions. Data was collected through participant observation of board of directors' and board of governors' meetings and narrative interviews from directors and governors of two NHS Foundation Trusts. Data was analyzed through thematic narrative analysis to enable the identification and understanding of the patterns and the hidden tensions in boards. FINDINGS: Findings reveal that board interactions are influenced strongly by the nexus of structural, contextual and human elements of governance. Three main findings are highlighted: a lack of clarity of the governors' and chairpersons' roles which create ambiguities within board processes; the large size of the board of governors disrupts meaningful discussions in board meetings; the unacceptability and avoidance of governors' accountability by the directors creates a struggle for supremacy and legitimacy in boards. RESEARCH LIMITATIONS/IMPLICATIONS: Future research can explore both the positive and negative outcomes of board behaviors, which are influenced by the perceived built-in tensions in governance structures. In addition, access to other spaces of governance, such as, subcommittee meetings and private board meetings can further enrich our understanding of board dynamics. ORIGINALITY/VALUE: This study attempts to uncover the neglected modes of interactions within boards through a combination of two disparate perspectives: board structures/composition and interactions through an ethnonarrative approach.
Assuntos
Conselho Diretor , Medicina Estatal , Humanos , Responsabilidade SocialRESUMO
BACKGROUND: Neurological disorders comprise a large group of clinically and genetically heterogeneous disorders, many of which have a genetic cause. In addition to a detailed neurological examination, exome sequencing is being increasingly used as a complementary diagnostic tool to identify the underlying genetic cause in patients with unclear, supposedly genetically determined disorders. OBJECTIVE: To identify the genetic cause of a complex movement disorder in five consanguineous Pakistani families. METHODS: We included five consanguineous Pakistani families with complex recessively inherited movement disorders. Clinical investigation including videotaping was carried out in a total of 59 family members (4-21 per family) and MRI in six patients. Exome sequencing was performed in 4-5 family members per pedigree to explore the underlying genetic cause. RESULTS: Patients presented a wide spectrum of neurological symptoms including ataxia and/or dystonia. We identified three novel homozygous, segregating variants in ATCAY (p.Pro200Profs*20), MCOLN1 (p.Ile184Thr), and SACS (p.Asn3040Lysfs*4) in three of the families. Thus, we were able to identify the likely cause of the disease in a considerable number of families (60%) with the relatively simple and nowadays widely available method of exome sequencing. Of note, close collaboration of neurologists and geneticists was instrumental for proper data interpretation. CONCLUSIONS: We expand the phenotypic, genotypic, and ethnical spectrum of mutations in these genes. Our findings alert neurologists that rare genetic causes should be considered in complex phenotypes regardless of ethnicity.
Assuntos
Proteínas de Choque Térmico/genética , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Proteínas do Tecido Nervoso/genética , Canais de Potencial de Receptor Transitório/genética , Adolescente , Adulto , Ataxia/diagnóstico por imagem , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Consanguinidade , Distonia/diagnóstico por imagem , Distonia/genética , Distonia/fisiopatologia , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico por imagem , Paquistão , Linhagem , Sequenciamento do Exoma , Adulto JovemRESUMO
Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician's dystonia (MD) and writer's dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A>G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson's disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias.