title: Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.
abstract: Data from massively parallel sequencing or 'Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening.
authors.affiliation: Program in Developmental Endocrinology and Genetics, Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
authors.forename: J L
authors.initials: JL
authors.lastname: Cross
authors.forename: J
authors.initials: J
authors.lastname: Iben
authors.forename: C L
authors.initials: CL
authors.lastname: Simpson
authors.forename: A
authors.initials: A
authors.lastname: Thurm
authors.forename: S
authors.initials: S
authors.lastname: Swedo
authors.forename: E
authors.initials: E
authors.lastname: Tierney
authors.forename: J E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: L G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: F D
authors.initials: FD
authors.lastname: Porter
authors.forename: C A
authors.initials: CA
authors.lastname: Wassif
mesh_terms: D000483:Alleles; D066264:Datasets as Topic; D005787:Gene Frequency; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015994:Incidence; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D019082:Smith-Lemli-Opitz Syndrome / Q000453:epidemiology* / Q000235:genetics*
chemical_list: D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase
keywords: DHCR7; SLOS; Smith-Lemli-Opitz; allelic frequency; next generation sequencing