When to think outside the autozygome: Best practices for exome sequencing in “consanguineous” families

Eaton, Alison; Hartley, Taila; Kernohan, Kristin D.; Itō, Yoko; Lamont, Ryan E.; Barrowman, Nick; Innes, A. Micheil; Boycott, Kym M.

doi:10.1111/cge.13736

Cited by 12 publications

(4 citation statements)

References 31 publications

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“…Our diagnostic yield was 53.8% using a singleton ES approach, which is in agreement with previously published studies reporting a diagnostic rate around 45%–50% in close consanguineous families 19–21. This high diagnostic yield is obtained through prioritising mainly homozygous variants (which are expected to be the cause in consanguineous couples) and also as a result of in-depth phenotyping.…”

Section: Discussionsupporting

confidence: 90%

“…Interestingly, our high diagnostic yield was achieved using a singleton approach given that the majority of causative variants identified in our cohort were homozygous. In this context, given that homozygous causative variants are detected straightforwardly by singleton ES, it is reasonable to support its use as a possible first tier in highly consanguineous families,19 considering cost-efficiency issues.…”

Section: Discussionmentioning

confidence: 99%

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Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples

et al. 2022

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BackgroundConsanguineous couples have an increased risk of severe diseases in offspring due to autosomal recessive disorders. Exome sequencing (ES) offers the possibility of extensive preconception carrier screening (PCS) in consanguineous couples who may be at risk of rare genetic disorders.MethodsWe retrospectively analysed ES data from 65 probands affected with rare genetic disorders born from consanguineous couples. We explored diagnostic yield and carrier status for recessive disorders.ResultsThe overall diagnostic yield in a singleton approach was 53.8%, mostly recessive variants. In a hypothetical exome-based PCS, only 11.7% of these causative rare variants would have been missed in the filtering process. Carrier screening for recessive conditions allowed the identification of at least one additional pathogenic or likely pathogenic variant in 85.7% of the probands, being the majority with a gene carrier frequency <1 in 200. In addition, considering only clinically actionable conditions, we estimated that 12.3% of our close consanguineous couples may be at risk for an additional recessive disease.ConclusionsOur results demonstrate that ES outperforms panel-based screening in a PCS context in consanguineous couples and could potentially increase their reproductive autonomy and facilitate informed decision-making.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples

et al. 2022

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“…All the members were of Hui nationality, and the parents of the patients were remote cousins. Homozygous variants accounted for a high rate of diagnoses in close and presumed consanguineous multiplex families with recessive inherited disease [32], suggesting us to consider the segregation of homozygous variants. The normal parents of HL05 were not consanguineously married and were of Han nationality from Shaanxi province in China.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss

Liang

Chen

Wang

et al. 2021

International Journal of Pediatric Otorhinolaryngology

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Background:Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identi ed as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families. Methods:After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were veri ed by Sanger sequencing in all patients and their parents. Results:Biallelic mutations were identi ed in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identi ed. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing con rmed that these mutations segregated with the hearing loss of each family. Conclusions:Next-generation sequencing (NGS) approach becomes more cost-effective and e cient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current ndings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive signi cance for genetic counseling. gene (14.5%) are the second common pathogenic cause of DFNB in addition to the GJB2 gene (17.9%) [8,9]. Sanger sequencing to detect mutations in GJB2 and SLC26A4 is a routine method during genetic testing and counseling for deafness patients. However, for GJB2 or SLC26A4-negative patients, especially those from small-sized recessive families, the potential genetic causes for deafness are yet unclear.The genetic heterogeneity of hearing loss, with about 152 deafness-associated genes, identi ed to be associated with NSHL [10], makes conventional polymerase chain reaction (PCR)-based Sanger sequencing impractical for large-scale gene detection because of its cost-ine ciency and timeconsumption [11]. In recent years, next-generation sequencing (NGS) approach may make it possible to analyze multiple genes, including all the deafness-associated genes, in one test [12]. Whole exome sequencing (WES), a platform of NGS, offers powerful applications for diagnosis as well as identifying rare variants or new causative genes [13,14].In this study, we utilized WES to investigate the contributing genetic factors in patients from six unrelated Chinese families with autosomal recessive hearing loss but did not harbor GJB2 and SLC26A4 mutations. MethodsSix unrelated Chinese families (code as HL01-06) were recruited from the outpatient clinic of the

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Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing of Six Chinese Families With Hereditary Non-Syndromic Hearing Loss: A Genetic Etiology Study

Liang

Chen²,

Wang

et al. 2020

Preprint

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Background: Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identified as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families.Methods: After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were verified by Sanger sequencing in all patients and their parents.Results: Biallelic mutations were identified in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identified. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family.Conclusions: Next-generation sequencing (NGS) approach becomes more cost-effective and efficient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current findings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive significance for genetic counseling.

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When to think outside the autozygome: Best practices for exome sequencing in “consanguineous” families

Cited by 12 publications

References 31 publications

Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples

Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples

Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss

Whole Exome Sequencing of Six Chinese Families With Hereditary Non-Syndromic Hearing Loss: A Genetic Etiology Study

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