title: Challenges and solutions for gene identification in the presence of familial locus heterogeneity.
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.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Atteeq U
authors.initials: AU
authors.lastname: Rehman
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Drummond
authors.affiliation: 1] National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan [2] Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Shahzad
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morell
authors.affiliation: 1] Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA [2] Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Abid
authors.initials: A
authors.lastname: Jan
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Aziz
authors.affiliation: 1] National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan [2] Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Gao T
authors.initials: GT
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Khitab
authors.initials: K
authors.lastname: Gul
authors.affiliation: Molecular Otolaryngology and Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: A Eliot
authors.initials: AE
authors.lastname: Shearer
authors.affiliation: Molecular Otolaryngology and Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Religious Studies, Michigan State University, East Lansing, MI, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hinnant
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Fisher
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: 1] Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA [2] Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Friderici
authors.affiliation: 1] National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan [2] Allama Iqbal Medical College-Jinnah Hospital Complex, University of Health Sciences, Lahore, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Wilch
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D044466:Asian People; D002135:Calcium-Binding Proteins / Q000235:genetics; D002874:Chromosome Mapping; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D034381:Hearing Loss / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000076988:Sulfate Transporters; D044465:White People
chemical_list: C577150:CIB2 protein, human; D002135:Calcium-Binding Proteins; D017630:Connexins; C066855:HGF protein, human; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D000072259:Connexin 26; D017228:Hepatocyte Growth Factor