Penetrance rate estimation in autosomal dominant conditions

Otto, Paulo Alberto; Horimoto, Andréa Roseli Vançan Russo

doi:10.1590/s1415-47572012005000051

Cited by 6 publications

(5 citation statements)

References 5 publications

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“…Using all available family kinship and phenotype information, the maximum likelihood estimation of penetrance and credible 95% interval for this pedigree is 0.96 (0.85-1.0) (See Supplementary Table 3). 23, 24 One subject (VI-1) had undergone heart transplantation (age 18). The mean age of death (N=11) or transplantation (N=1) was 46.1 ± 17.3 years.…”

Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree With Familial Dilated Cardiomyopathy

Wells

Becker

et al. 2013

Circ Cardiovasc Genet

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Background Whole exome sequencing (WES) is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied WES to identify the causal variant in a large family with familial dilated cardiomyopathy (DMC) of unknown etiology. Methods and Results A large family with autosomal dominant, familial DCM was identified. Exome capture and sequencing was performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool (VAAST). Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency ≤ 0.001 or not reported) in two public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with VAAST supported this result. Conclusions WES of remotely related DCM subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis.

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Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree With Familial Dilated Cardiomyopathy

Wells

Becker

et al. 2013

Circ Cardiovasc Genet

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“…Although there are no gold standard measurement techniques, crude penetrance estimates for a specific genotype can be derived from a disease population by dividing the observed number of individuals with the disease (penetrant) by the total number of obligate carriers (non-penetrant and penetrant). 34 In UK MND cohorts, this has revealed a high penetrance for some SOD1 (e.g., A5V) and FUS variants, 28 but significantly incomplete penetrance for the C9ORF72 hexanucleotide repeat expansion. 33 However, penetrance is clearly age-dependent, with near complete expression (99.5%) of the phenotype reported by 83 years for Pedigree showing an autosomal dominant inheritance of ALS.…”

Section: Incomplete Penetrancementioning

confidence: 99%

Genetic testing in motor neurone disease

et al. 2022

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A minority (10%–15%) of cases of amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), are currently attributable to pathological variants in a single identifiable gene. With the emergence of new therapies targeting specific genetic subtypes of ALS, there is an increasing role for routine genetic testing for all those with a definite diagnosis. However, potential harm to both affected individuals and particularly to asymptomatic relatives can arise from the indiscriminate use of genetic screening, not least because of uncertainties around incomplete penetrance and variants of unknown significance. The most common hereditary cause of ALS, an intronic hexanucleotide repeat expansion in C9ORF72, may be associated with frontotemporal dementia independently within the same pedigree. The boundary of what constitutes a possible family history of MND has therefore extended to include dementia and associated psychiatric presentations. Notwithstanding the important role of clinical genetics specialists, all neurologists need a basic understanding of the current place of genetic testing in MND, which holds lessons for other neurological disorders.

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“…Several methods exist for penetrance estimation. The first and most widely used is based on statistical examination of how the variant segregates with the phenotype within pedigrees [ 7 ]. However, the generalisability of estimates derived from specific families may be limited.…”

Section: Introductionmentioning

confidence: 99%

Calculating variant penetrance from family history of disease and average family size in population-scale data

et al. 2022

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Background Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical fields including genetic counselling, disease research, and gene therapy. However, existing approaches for penetrance estimation require, for instance, large family pedigrees or availability of large databases of people affected and not affected by a disease. Methods We present a method for penetrance estimation in autosomal dominant phenotypes. It examines the distribution of a variant among people affected (cases) and unaffected (controls) by a phenotype within population-scale data and can be operated using cases only by considering family disease history. It is validated through simulation studies and candidate variant-disease case studies. Results Our method yields penetrance estimates which align with those obtained via existing approaches in the Parkinson’s disease LRRK2 gene and pulmonary arterial hypertension BMPR2 gene case studies. In the amyotrophic lateral sclerosis case studies, examining penetrance for variants in the SOD1 and C9orf72 genes, we make novel penetrance estimates which correspond closely to understanding of the disease. Conclusions The present approach broadens the spectrum of traits for which reliable penetrance estimates can be obtained. It has substantial utility for facilitating the characterisation of disease risks associated with rare variants with an autosomal dominant inheritance pattern. The yielded estimates avoid any kinship-specific effects and can circumvent ascertainment biases common when sampling rare variants among control populations.

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Penetrance rate estimation in autosomal dominant conditions

Cited by 6 publications

References 5 publications

Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree With Familial Dilated Cardiomyopathy

Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree With Familial Dilated Cardiomyopathy

Genetic testing in motor neurone disease

Calculating variant penetrance from family history of disease and average family size in population-scale data

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