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1.
Am J Hum Genet ; 110(1): 105-119, 2023 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-36493768

RESUMEN

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.


Asunto(s)
Ataxia Cerebelosa , Factores de Crecimiento de Fibroblastos , Ataxia de Friedreich , Expansión de Repetición de Trinucleótido , Adulto , Humanos , Ataxia/genética , Australia , Ataxia Cerebelosa/genética , Ataxia de Friedreich/genética , Expansión de Repetición de Trinucleótido/genética
2.
Ann Neurol ; 92(1): 122-137, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35411967

RESUMEN

OBJECTIVE: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus. METHODS: Whole-exome and whole-genome sequencing were performed in families linked to SCA25, including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology. RESULTS: The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25. An additional nonsense variant was detected in an unrelated individual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1-domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double-stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response. INTERPRETATION: This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022;92:122-137.


Asunto(s)
Ataxia Cerebelosa , Interferón Tipo I , Ataxias Espinocerebelosas , Ataxia , Australia , Exorribonucleasas , Francia , Humanos , Interferón Tipo I/genética , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología
4.
Genome Med ; 15(1): 74, 2023 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-37723522

RESUMEN

BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.


Asunto(s)
Síndromes Neoplásicos Hereditarios , Humanos , Estudios Prospectivos , Oncogenes , Pruebas Genéticas , Células Germinativas
7.
Eur J Med Genet ; 63(1): 103618, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30684669

RESUMEN

A small heterozygous deletion involving KANK1 was originally reported in 2005 to cause cerebral palsy in one large Israeli family of Jewish Moroccan origin. There were nine affected children over two generations to five unaffected fathers. All of these children had congenital hypotonia that evolved into spastic quadriplegia over the first year of life, along with intellectual impairment and brain atrophy. The subsequent clinical depictions of other individuals with neurological disease harbouring a comparable KANK1 deletion have been extremely variable and most often quite dissimilar to the original family. The reported pathogenicity of these deletions has also been variable, due to an inconsistent nature of reported disease associations and limited data. We therefore sought to perform a review of the significance of small distal interstitial chromosome 9p24.3 deletions principally involving KANK1, including data from the VCGS cytogenetics laboratory. We found that carrier parents do not appear to display an increased frequency of neurological disease, individuals with a small KANK1 deletion have sometimes been found to have an alternate genetic diagnosis that explained their neurological condition, and small KANK1 deletions can be seen with approximate equal frequency in case and control populations. These data led us to conclude that small deletions involving KANK1 do not cause a highly-penetrant influence of large effect size and they are unlikely to contribute significantly to the aetiology of disease in patients with development delay, intellectual disability, autism or cerebral palsy. We recommend searching for an alternate explanation for disease in individuals with a neurological disorder found to have a small deletion involving KANK1.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Parálisis Cerebral/genética , Proteínas del Citoesqueleto/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Parálisis Cerebral/patología , Niño , Preescolar , Cromosomas Humanos Par 9/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/patología , Masculino , Linaje , Eliminación de Secuencia/genética , Adulto Joven
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