ArticleEuropean journal of human genetics : EJHG2015
Challenges and solutions for gene identification in the presence of familial locus heterogeneity.
Article in European journal of human genetics : EJHG, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 38 citations in OpenAlex.
- Genetic studies identify known and novel variants for recessively inherited moderate to severe hearing loss in consanguineous families from Pakistan.Scientific reports · 2026Article
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- Genetic heterogeneity in hereditary hearing loss: Potential role of kinociliary protein TOGARAM2.European journal of human genetics : EJHG · 2024Article
- Genome sequencing identifies coding and non-coding variants for non-syndromic hearing loss.Journal of human genetics · 2023Article
- Molecular genetic landscape of hereditary hearing loss in Pakistan.Human genetics · 2022Review
- Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings.Human genetics · 2022Review
- Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Article
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- Otitis media susceptibility and shifts in the head and neck microbiome due toJournal of medical genetics · 2021Article
- Exome sequencing utility in defining the genetic landscape of hearing loss and novel-gene discovery in Iran.Clinical genetics · 2021Article
- Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies.Genes · 2021Article
- Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss.Molecular biology reports · 2020Article
- Multi-omic studies on missense PLG variants in families with otitis media.Scientific reports · 2020Article
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- A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.Human mutation · 2019Article
- Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.Human mutation · 2019Article
- FUT2 Variants Confer Susceptibility to Familial Otitis Media.American journal of human genetics · 2018Article
- Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.Human genetics · 2018Article
- Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.The Journal of clinical investigation · 2018Article
- Unresolved questions regarding human hereditary deafness.Oral diseases · 2017Review
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Authors and funding
30 authors at 12 institutions in 2 countries.
Funding
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.
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Registered trials
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