Statistical pitfalls in detecting age-of-onset anticipation

Se, Hodge; Wickramaratne, Pryia J.

doi:10.1097/00041444-199521000-00007

Cited by 48 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It thus seems likely that many of these reports of apparent anticipation, were indeed artefacts of the very real ascertainment biases first delineated by Pearson [23] and later expounded upon by Penrose [35]. Indeed, even after the discovery of unstable DNA, a lively debate ensued about how to fully correct for these ascertainment biases, in particular with regard to reports of anticipation in bi-polar affective disorder and schizophrenia (e.g., [78][79][80][81][82][83][84][85]). Of course, it also remains possible that there are other causes of genuine anticipation, such as for instance might be mediated by time dependent changes in environmental exposures, as has been proposed to account for the apparent anticipation observed in familial amyloidotic polyneuropathy type I for which the mutation is known to be a very static missense variant in the transthyretin gene [86].…”

Section: In From the Cold: Anticipation Legitimisedmentioning

confidence: 99%

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Monckton

2021

JHD

View full text Add to dashboard Cite

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

show abstract

Section: In From the Cold: Anticipation Legitimisedmentioning

confidence: 99%

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Monckton

2021

JHD

View full text Add to dashboard Cite

show abstract

Anticipation in schizophrenia: Biology or bias?

et al. 1997

View full text Add to dashboard Cite

Anticipation is a genetic phenomenon wherein age of disease onset decreases and/ or severity increases in successive generations. Anticipation has been demonstrated for several neuropsychiatric disorders with expanding trinucleotide repeats recently identified as the underlying molecular mechanism. We report here the results of an analysis of anticipation performed with multiplex families segregating schizophre-nia. Thirty-three families were identified through the NIMH Genetics Initiative that met the following criteria: had at least two affected members in successive generations and were not bilineal. Affectation diagnoses included schizophrenia, schizoaffective disorder depressed , and psychosis NOS. Additional analyses included the Cluster A personality disorders. Three indices of age of onset were used. Disease severity was measured by several different indices. Four sampling schemes as suggested by McInnis et al. were tested, as well as additional analysis using pairs ascertained through the parental generation. Anticipation was demonstrated for age of onset, regardless of the index or sampling scheme used (P<0.05). Anticipation was not supported for disease severity. Analyses that took into account drug use and diminished fecundity did not affect the results. While the data strongly support intergenerational differences in disease onset consistent with anticipation, they must be viewed cautiously given unavoidable biases attending these analyses.

show abstract

Anticipation in schizophrenia: No evidence of expanded CAG/CTG repeat sequences in French families and sporadic cases

et al. 1998

View full text Add to dashboard Cite

A decrease in age of onset of schizophrenia through consecutive family generations (anticipation) has been found in several studies. Anticipation is known to result from expansion of CAG repeats in genes that determine several neurodegenerative disorders. In a previous study we analysed 26 unilineal two-generation French pedigrees and found clinical evidence of anticipation. A 10-year mean reduction in age of onset of schizophrenia was found in the second generation compared with the parental generation. The repeat expansion detection method was used to screen for CAG expansion in 21 of the 26 families with evidence of anticipation for the disease and in 59 sporadic schizophrenics and 59 controls. Comparison of the frequency distributions of CAG/CTG repeat size observed in schizophrenics and controls showed no significant difference, even when we considered familial (P = 0.23) and sporadic (P = 0.25) affected individuals separately. These results do not support the association between long CAG repeats and schizophrenia. However, the possibility that expansions with fewer than 40 repeats are involved in schizophrenia cannot be excluded.

show abstract

Statistical pitfalls in detecting age-of-onset anticipation

Cited by 48 publications

References 0 publications

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Anticipation in schizophrenia: Biology or bias?

Anticipation in schizophrenia: No evidence of expanded CAG/CTG repeat sequences in French families and sporadic cases

Contact Info

Product

Resources

About