Abstract
BackgroundSmith–Lemli–Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2–3 syndactyly of the toes. SLOS is caused by defective 7-dehydrocholesterol reductase, which is encoded by the DHCR7 gene. This study aimed to analyze the carrier frequency and expected incidence of SLOS in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD) through the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline (2015 ACMG-AMP guideline).MethodsWe analyzed 9197 exomes for East Asian populations from gnomAD, comprising 1909 Korean, 76 Japanese, and 7212 other East Asian populations. All identified variants were classified according to the 2015 ACMG-AMP guideline.ResultsAccording to the 2015 ACMG-AMP guideline, 15 pathogenic variant/likely pathogenic variant (PV/LPV) cases were identified in 33 East Asian individuals (33/9191 = 0.4%). Among them, four PVs/LPVs were identified in 19 Korean individuals (19/1909 = 1.0%). The predicted incidence, based upon the carrier rates of PV/LPV of DHCR7 alleles, is 1 in 310,688 in East Asians and l in 40,380 in Koreans.ConclusionsThis study is the first to identify carrier frequencies in East Asians and Koreans using gnomAD. It was confirmed that East Asians (0.4%) had a lower carrier frequency than did other ethnicities (1–3%) and Koreans (1.0%) had similar or lower carrier frequencies than other ethnicities. The variant spectrums of DHCR7 in East Asian and Korean populations differed greatly from those of other ethnic groups.
Highlights
Smith–Lemli–Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2–3 syndactyly of the toes
In 1909 Korean exomes there were 16 variants, of which 15 were missense and one was nonsense. These variants were classified according to the 2015 ACMGAMP guideline and two disease classification databases, Human Gene Mutation Database (HGMD) and ClinVar (Table 1)
According to the 2015 American College of Medical Genetics (ACMG)-Association for Molecular Pathology (AMP) guideline, 15 pathogenic variant (PV)/ Likely pathogenic variant (LPV) cases were identified in 33 East Asian individuals (33/9191 = 0.4%)
Summary
Smith–Lemli–Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2–3 syndactyly of the toes. Smith–Lemli–Opitz syndrome (SLOS, OMIM #270,400) is an autosomal, recessively inherited congenital malformation syndrome, which is an inborn error of cholesterol. SLOS incidence has been reported to be between 1/10,000 and 1/70,000 in populations, primarily studied in Caucasians, while its incidence in East Asians is not well known [4, 5]. Based on the c.964-1G > C variant, the most common pathogenic variant in SLOS, the carrier frequency is known to be approximately 1% in Caucasians, but up to 3% has been reported [6,7,8]. Carrier frequency studies are extremely rare in the East Asian population. The cumulative carrier frequency of 13,546 East Asians, who performed elected expanded carrier screening, was 0.1% [10]
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