Smith-Lemli-Opitz Syndrome via the DHCR7 Gene

Smith-Lemli-Opitz syndrome (SLOS) (OMIM 270400) is a deficiency in the enzyme 7-dehydrocholesterol reductase, which catalyzes the last step in the biosynthesis of cholesterol. Affected children have high plasma 7-dehydrocholesterol/cholesterol ratios. The enzyme deficiency leads to a variety of developmental problems including growth and mental retardation, 2-3 toe syndactyly, microcephaly, anteverted nares, ptosis, genital abnormalities, heart defects, polydactyly, and photosensitivity. The most severe cases are usually diagnosed in infancy, with milder cases diagnosed in childhood or even adult life. The great majority of SLOS patients have some clinical features of autism (Sikora et al. Am J Med Genet A 140A:1511-1518, 2006).

Smith-Lemli-Opitz syndrome (SLOS) exhibits autosomal recessive inheritance. Variants in the DHCR7 gene encoding 7-dehydrocholesterol reductase are the only known cause of SLOS. About 130 causative DHCR7 variants have been reported to date (Witsch- Baumgartner et al. Hum Mut 17:172-182, 2001; Correa-Cerro and Porter. Mol Genet Metab 84:112-126, 2005). About 90% of these variants are missense, although “gene knockout” variants (splicing, nonsense, and frameshift) are also known. Among those with European ancestry, the most common variants appear to be c.964-1G>C (IVS8-1G>C), p.Thr93Met, p.Trp151*, p.Arg404Cys, and p.Val326Leu. Carrier rates for SLOS in some populations may be as high as 1/30. Missed diagnoses and especially spontaneous miscarriages may explain the difference between the expected incidence based on carrier rates and the actual incidence of roughly 1/30,000 (Nowaczyk et al. Am J Med Genet A 140A:2057-62, 2006).

Using DNA sequencing and characterizing patients by plasma sterol concentrations and clinical features, Witsch-Baumgartner et al. (2000) detected two likely causative variants in 78 out of 84 (93%) SLOS patients and one likely causative variant in the remaining 6 (7%).

This test provides full coverage of all coding exons of the DHCR7 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).