Carrier testing for severe childhood recessive diseases by next-generation sequencing.

Sci Transl Med 2011 Jan;3(65):65ra4

National Center for Genome Resources, Santa Fe, NM 87505, USA.

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 160x average target coverage, 93% of nucleotides had at least 20x 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.

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.3001756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740116PMC
January 2011
53 Reads

Publication Analysis

Top Keywords

severe recessive
12
preconception screening
8
recessive childhood
8
next-generation sequencing
8
carrier burden
8
recessive diseases
8
carrier testing
8
severe
6
recessive
6
carrier
6
sensitivity ~100%
4
mutation detection/genotyping
4
detection/genotyping ~95%
4
~95% sensitivity
4
coverage mutation
4
20x coverage
4
nucleotides 20x
4
~100% specificity
4
93% nucleotides
4
coverage 93%
4

References

(Supplied by CrossRef)

Myrianthopoulos et al.
American journal of human genetics 1966

Mitchell et al.
American journal of human genetics 1996

Kronn et al.
Archives of Internal Medicine 1998

European journal of pediatrics 2000

Costa et al.
American journal of medical genetics 1985

Kumar et al.
Mayo Clinic Proceedings 2001

Obstetrics & Gynecology 2009

Obstetrics & Gynecology 2006

Obstetrics & Gynecology 2005

Grody et al.
Genetics in medicine : official journal of the American College of Medical Genetics 2001

Genetics in medicine : official journal of the American College of Medical Genetics 2006

Similar Publications