Automatic Selection ofLoop Breakers for GeneticLinkage Analysis

Becker, Ann; Geiger, Dan; Schäffer, Alejandro A.

doi:10.1159/000022781

Cited by 46 publications

(35 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The parameters SNP allele frequencies, penetrance, disease frequency, and phenocopy rate were set at 0.5 for both major and minor allele, 95%, 0.001, and 0.00, respectively. Subsequently, two-point linkage analyses were performed assessing the likelihood of association between the rare synonymous LMNA variant and disease (FASTLINK v4.1P) (36). SNP allele frequency (major allele frequency/ minor allele frequency), penetrance, disease frequency, and phenocopy rate were set at 0.999/0.001, 95%, 0.001, and 0.00, respectively.…”

Section: Dna Sequencing and Genotyping For Mae/man Familymentioning

confidence: 99%

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Ito

Patel

Gorham

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Genetic variants that cause haploinsufficiency account for many autosomal dominant (AD) disorders. Gene-based diagnosis classifies variants that alter canonical splice signals as pathogenic, but due to imperfect understanding of RNA splice signals other variants that may create or eliminate splice sites are often clinically classified as variants of unknown significance (VUS). To improve recognition of pathogenic splice-altering variants in AD disorders, we used computational tools to prioritize VUS and developed a cell-based minigene splicing assay to confirm aberrant splicing. Using this two-step procedure we evaluated all rare variants in two AD cardiomyopathy genes, lamin A/C (LMNA) and myosin binding protein C (MYBPC3). We demonstrate that 13 LMNA and 35 MYBPC3 variants identified in cardiomyopathy patients alter RNA splicing, representing a 50% increase in the numbers of established damaging splice variants in these genes. Over half of these variants are annotated as VUS by clinical diagnostic laboratories. Familial analyses of one variant, a synonymous LMNA VUS, demonstrated segregation with cardiomyopathy affection status and altered cardiac LMNA splicing. Application of this strategy should improve diagnostic accuracy and variant classification in other haploinsufficient AD disorders.D NA sequence analysis of patient DNA has been used to clinically diagnose associated inherited diseases, leading to the identification of thousands of rare sequence variants in affected and unaffected individuals. Interpreting the medical significance of these variants has proven to be a significant challenge. The annotation of nonsense, frameshift, insertion, and deletion variants that cause a highly predictable outcome [i.e., loss of function (LoF) of proteins encoded by disease genes] allows these to be clinically classified as pathogenic variants in more than 4,000 genes that cause disease by haploinsufficiency (1). Classification of rare synonymous and missense variants in these genes, however, has been more difficult. Although bioinformatic algorithms predict that some variants may damage the encoded protein, these annotations are imperfect, and many rare variants remain unclassified and are clinically designated as variants of unknown significance (VUS) (2).Splicing signals reside at all exon-intron junctions and include a 9-bp 5′ splice donor sequence with an invariant GT dinucleotide and a 23-bp 3′ splice acceptor sequence with an invariant AG dinucleotide (3) (Fig. 1A). Variants that alter the canonical GT and AG dinucleotides in haploinsufficient autosomal dominant (AD) genes are diagnostically classified as pathogenic, whereas substitutions of the remaining seven residues within the donor sequence, or the 21 residues within the acceptor sequence, are often classified as VUS (4). VUS that alter these sequences, however, have the potential to disrupt normal RNA splicing (5) (resulting in donor or acceptor loss; Fig. 1C). Similarly, variants within a nearby intron or exon may sufficiently mimic the consensus donor...

show abstract

Section: Dna Sequencing and Genotyping For Mae/man Familymentioning

confidence: 99%

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Ito

Patel

Gorham

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Both pairwise and multipoint lod score linkage analyses, performed with FASTLINK version 4.1 46,47 were used to analyze the four data set configurations (Sets 1 and 2, and pedigrees B and BVG). For the pairwise analysis, both reduced-penetrant dominant (described above) and recessive modes of inheritances were used in a full genome scan.…”

Section: Linkage Analysesmentioning

confidence: 99%

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q

et al. 2003

View full text Add to dashboard Cite

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The 'ideal' features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic 'bottleneck' in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

show abstract

“…Methods for finding and cutting loops have been developed for human pedigrees [6][7][8], and for complex animal pedigrees [5,9]. The method introduced by Xie and Ott [6] uses a graph strategy, called depth-first search, that examines exhaustively the whole pedigree in order to identify a set of loops.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Becker et al [7] treated the problem of selecting loop breakers. They showed, as did also O'Connell and Weeks [10], that the selection of loop breakers has a significant impact on the computational running time of the subsequent likelihood computation.…”

Section: Introductionmentioning

confidence: 99%

Selecting Loop Breakers in General Pedigrees

Vitezica

Mongeau²,

Manfredi

et al. 2004

Hum Hered

View full text Add to dashboard Cite

The presence of loops in pedigrees poses severe computational problems in likelihood calculation that can be solved by creating an equivalent unlooped pedigree. We introduce a heuristic polynomial-time dynamic-programming algorithm, called SFH, that addresses the problem of selecting a minimal-cost set of loop breakers. We report computational experiments on simulated pedigrees with up to 1000 individuals and 361 loops, and multiple marriages. We compare the loop-breaker set selected by our method with that obtained using the software package FASTLINK 4.1P. Our approach outperforms FASTLINK 4.1P on the computational-time point of view, on the point of view of quality of the loop-breaker set obtained, and on the point of view of the size of the problem that can be addressed.

show abstract

Automatic Selection ofLoop Breakers for GeneticLinkage Analysis

Cited by 46 publications

References 17 publications

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q

Selecting Loop Breakers in General Pedigrees

Contact Info

Product

Resources

About