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Determination of the allelic frequency in Smith–Lemli–Opitz syndrome by analysis of massively parallel sequencing data sets
Author(s) -
Cross J.L.,
Iben J.,
Simpson C.L.,
Thurm A.,
Swedo S.,
Tierney E.,
BaileyWilson J.E.,
Biesecker L.G.,
Porter F.D.,
Wassif C.A.
Publication year - 2015
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12425
Subject(s) - exome sequencing , massive parallel sequencing , exome , genetics , smith–lemli–opitz syndrome , biology , allele frequency , allele , medical genetics , single nucleotide polymorphism , population , snp , dna sequencing , gene , medicine , mutation , genotype , reductase , 7 dehydrocholesterol reductase , biochemistry , environmental health , enzyme
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.