Smith–Lemli–Opitz syndrome carrier frequency and estimates of in utero mortality rates

Abstract

ObjectiveTo tabulate individual allele frequencies and total carrier frequency for Smith–Lemli–Opitz syndrome (SLOS) and compare expected versus observed birth incidences.MethodsA total of 262 399 individuals with no known indication or increased probability of SLOS carrier status, primarily US based, were screened for SLOS mutations as part of an expanded carrier screening panel. Results were retrospectively analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature were then compared with these data to estimate the effect of SLOS on fetal survival.ResultsSmith–Lemli–Opitz syndrome carrier frequency is highest in Ashkenazi Jews (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence with that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience prenatal demise.ConclusionSmith–Lemli–Opitz syndrome is relatively frequent in certain populations and, because of its impact on prenatal and postnatal morbidity and mortality, merits consideration for routine screening. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Carrier frequency and incidence estimation of Smith–Lemli–Opitz syndrome in East Asian populations by Genome Aggregation Database (gnomAD) based analysis

“…Based on disease classification databases, HGMD and ClinVar, carrier frequencies were 0.2–0.3% in East Asians and 0.6% in Koreans. Compared with previous studies on East Asians, carrier frequency in gnomAD is located between the previous reports (0.1 to 1.6%) [ 9 , 10 ].…”

“…As the 2015 ACMG-AMP guideline is more stringent in variant classification, a previous study has shown a relatively higher carrier frequency than this. In another study, 13,546 East Asians were analyzed, of which 3102 East Asians were analyzed using next-generation sequencing (NGS), and another 10,444 were analyzed using targeted genotyping that could only identify 13 major DHCR7 variants [ 10 ]. The carrier detection rate according to the method difference was different for each ethnic group.…”

“…One such study was carried out using large-scale data, including 1000 Genomes phase 1 with 286 East Asians, and the carrier frequency of East Asians was reported to be 1.6% [ 9 ]. Moreover, the cumulative carrier frequency of 13,546 East Asians, who performed elected expanded carrier screening, was 0.1% [ 10 ].…”

“…Recent studies on the genetic cause of stillbirth have reported associations with SLOS [ 11 ]. A difference exists between the expected incidence of SLOS and its actual incidence; this is estimated to be different as approximately 42–88% of affected conceptuses experience prenatal death [ 10 ]. Moreover, exposure to drugs such as aripiprazole or trazodone increases 7-DHC concentration, thus increasing the vulnerability of the DHCR7 variant carrier; and this is estimated to affect fetal development during pregnancy [ 12 , 13 ].…”

Clinical impact and cost-effectiveness of a 176-condition expanded carrier screen

“…Clinical specificity is expected to be high, 28 and even if clinical sensitivity were <100%, the results of our cost-effectiveness analysis would not be impacted because the clinical benefit measurements (i.e., the denominator in the cost-effectiveness equation) rely only on variants known to be pathogenic and are not affected by the undetected or incorrectly classified pathogenic variants that decrease clinical sensitivity. Third, though miscarriage can be common for certain diseases (e.g., Smith–Lemli–Opitz syndrome 40 ) and may impact cost estimates, we expect this impact to be minor because few diseases and variants yield higher miscarriage rates.…”