Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing

By C. Bell, D. Dinwiddie, Neil A. Miller, Shannon Hateley, E. Ganusova, J. Mudge, R. J. Langley, Lu Zhang, Clarence C Lee, Faye D. Schilkey and 6 more. 2011

657 citations recorded by the source corpus.

Carrier testing for 448 severe childhood recessive diseases by next-generation sequencing has good predictive value and suggests that every individual carries about three disease mutations. Shining a Light on Comprehensive Carrier Screening Although diseases inherited in a Mendelian fashion are rare, together they account for about 20% of deaths in infancy. For Mendelian diseases that are recessive (of which there are more than 1000), screening before pregnancy (preconception screening) together with genetic counseling of those carrying a mutant allele could reduce the incidence of these diseases and the suffering that they incur. In the case of Tay-Sachs disease, an incurable neurodegenerative disease of infancy, preconception screening for disease gene mutations and genetic counseling among individuals of Ashkenazi descent has reduced the incidence of this tragic disease by 90%. However, simultaneous testing for many recessive childhood diseases is costly, so, to date, screening has included just a few diseases such as Tay-Sachs disease, cystic fibrosis, and familial dysautonomia. In a new study, Kingsmore and his colleagues have combined target gene capture and enrichment, next-generation sequencing, and sophisticated bioinformatic analysis to develop a platform capable of screening several hundred DNA samples simultaneously for 448 severe recessive diseases of childhood. They demonstrate that their method is sensitive, specific, and scalable in a research setting and that it should be straightforward to automate the process. The authors report that individuals in the general population carry an average of three recessive childhood disease mutations. They also discovered that about 10% of disease mutations in commonly used databases are incorrect, suggesting that disease mutation annotations in such databases should be carefully scrutinized. The authors predict that their screening test could be made faster and more cost-effective with the advent of microdroplet polymerase chain reaction and third-generation sequencing technologies. Their study provides a proof of concept that it should be possible to introduce preconception carrier screening for many recessive pediatric disease mutations as long as the disease genes are known. Many social, legal, and societal issues need to be addressed before preconception carrier screening can be made available for the general population, and cost is still a big consideration. However, this methodology could also be applied for comprehensive screening of newborns and would allow early diagnosis and intervention for a variety of Mendelian diseases. Although it may be some time before preconception carrier testing enters the community setting, physicians, patients, parents, and genetic counselors need to discuss the impact and implications of this new technology. Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160× average target coverage, 93% of nucleotides had at least 20× coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.

Subfields: Genetics, Immunology, Pulmonary and Respiratory Medicine

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Citations in the corpus

Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. (2012, background): “Despite this, the variant is evidently nonpathogenic in some populations, such as the YRI, yet is regarded as pathogenic in other populations.(4) One explanation for this apparent contradiction could be that in the YRI population, the USH2A locus is subject to copy-number variation(38) that could ei”
The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies (2017, positive): “In a clinical setting, HGMD is widely utilised by many groups in ongoing NGS diagnostic (Bell et al. 2011; John-ston et al. 2012; Calvo et al. 2012; Makrythanasis et al. 2014; Karageorgos et al. 2015; Wilfert et al. 2016; Walsh et al. 2017) and human genome sequencing (Tong et al. 2010; Kim et al.…”
ACMG clinical laboratory standards for next-generation sequencing (2013, background): “It is well known that many databases contain misclassified variants, particularly benign variation misclassified as disease causing (Bell et al. 2011).”
InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines. (2017, background): “Similarly, Bell et al.51 found that 27% of the pathogenic variants cited in the literature are common polymorphisms or misannotated, underscoring the need for better mutation databases.”
The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine (2013, positive): “In a clinical setting, HGMD is widely utilized by many groups in ongoing NGS diagnostic (Johnston et al. 2012, Calvo et al. 2012, Bell et al. 2011) and human genome sequencing (Tong et al. 2010; Kim et al. 2009) programmes.”
ClinPred: Prediction Tool to Identify Disease-Relevant Nonsynonymous Single-Nucleotide Variants. (2018, background): “7 These incorrect annotations resulted from varying and inconsistent levels of evidence applied by different laboratories to determine causation.”