Limits...
Challenges and solutions for gene identification in the presence of familial locus heterogeneity.

Rehman AU, Santos-Cortez RL, Drummond MC, Shahzad M, Lee K, Morell RJ, Ansar M, Jan A, Wang X, Aziz A, Riazuddin S, Smith JD, Wang GT, Ahmed ZM, Gul K, Shearer AE, Smith RJ, Shendure J, Bamshad MJ, Nickerson DA, University of Washington Center for Mendelian GenomicsHinnant J, Khan SN, Fisher RA, Ahmad W, Friderici KH, Riazuddin S, Friedman TB, Wilch ES, Leal SM - Eur. J. Hum. Genet. (2014)

Bottom Line: However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology.We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data.Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

No MeSH data available.


Related in: MedlinePlus

Workflow for identification of causal variants in families with Mendelian traits.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4538203&req=5

fig4: Workflow for identification of causal variants in families with Mendelian traits.

Mentions: In summary, we demonstrate that linkage analysis and homozygosity mapping are still useful in the age of NGS. Although families presented here have HI, the proposed strategies discussed here and outlined in Figure 4 should be applicable to any Mendelian trait. In the presence of intra-familial locus heterogeneity, the causal variants may be identified by: (1) initial screening of genes that are known to harbor disease-causal variants; (2) use of additional clinical information that may give phenotypic clues to genetic etiology; (3) when locus heterogeneity is suspected, performing simulation and linkage analysis or homozygosity mapping for branches or subsets of individuals in order to identify individuals most likely to share the same disease-causal variant; (4) using linkage and haplotype information to select DNA samples from affected individuals for NGS; and (5) considering locus heterogeneity when evaluating co-segregation of variant with phenotype within the family. We have shown that occurrence of intra-familial locus heterogeneity, including intra-sibship heterogeneity, is not rare and that taking intra-familial locus heterogeneity into account while analyzing pedigree data can increase the success rate in the identification of causal variants for Mendelian traits. Although we have concentrated on demonstrating the presence of locus heterogeneity in pedigrees segregating Mendelian disease, this problem is not unique to Mendelian traits but also occurs in families segregating complex traits particularly in those with bilineal inheritance.


Challenges and solutions for gene identification in the presence of familial locus heterogeneity.

Rehman AU, Santos-Cortez RL, Drummond MC, Shahzad M, Lee K, Morell RJ, Ansar M, Jan A, Wang X, Aziz A, Riazuddin S, Smith JD, Wang GT, Ahmed ZM, Gul K, Shearer AE, Smith RJ, Shendure J, Bamshad MJ, Nickerson DA, University of Washington Center for Mendelian GenomicsHinnant J, Khan SN, Fisher RA, Ahmad W, Friderici KH, Riazuddin S, Friedman TB, Wilch ES, Leal SM - Eur. J. Hum. Genet. (2014)

Workflow for identification of causal variants in families with Mendelian traits.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538203&req=5

fig4: Workflow for identification of causal variants in families with Mendelian traits.
Mentions: In summary, we demonstrate that linkage analysis and homozygosity mapping are still useful in the age of NGS. Although families presented here have HI, the proposed strategies discussed here and outlined in Figure 4 should be applicable to any Mendelian trait. In the presence of intra-familial locus heterogeneity, the causal variants may be identified by: (1) initial screening of genes that are known to harbor disease-causal variants; (2) use of additional clinical information that may give phenotypic clues to genetic etiology; (3) when locus heterogeneity is suspected, performing simulation and linkage analysis or homozygosity mapping for branches or subsets of individuals in order to identify individuals most likely to share the same disease-causal variant; (4) using linkage and haplotype information to select DNA samples from affected individuals for NGS; and (5) considering locus heterogeneity when evaluating co-segregation of variant with phenotype within the family. We have shown that occurrence of intra-familial locus heterogeneity, including intra-sibship heterogeneity, is not rare and that taking intra-familial locus heterogeneity into account while analyzing pedigree data can increase the success rate in the identification of causal variants for Mendelian traits. Although we have concentrated on demonstrating the presence of locus heterogeneity in pedigrees segregating Mendelian disease, this problem is not unique to Mendelian traits but also occurs in families segregating complex traits particularly in those with bilineal inheritance.

Bottom Line: However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology.We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data.Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

No MeSH data available.


Related in: MedlinePlus