Submission Details

The relationship between the DHCR7 gene and autosomal recessive Smith-Lemli-Opitz syndrome (SLOS) is well-characterized, with over 150 unique variants described, including nonsense, missense, splice, and deletion variants reported in dozens of publications (GeneReviews: Smith-Lemli-Opitz Syndrome - GeneReviews® - NCBI Bookshelf (nih.gov)). Smith-Lemli-Opitz is characterized by a spectrum of affectedness with the most commonly reported features being delayed growth (including fetal growth restriction), microcephaly, and mild to severe intellectual disability. Other features such as polydactyly, facial dysmorphisms, cardiac defects, renal hypoplasia, increased fetal nuchal translucency, and abnormalities of male genitalia are also common.

Based on a known carrier frequency, there is a lower observed disease prevalence than expected, possibly suggesting increased rates of pregnancy loss in carrier couples SLOS or subclinical presentation of the disease in affected individuals (PMIDs: 28166604, 20556518). There are a few discrepant publications to make such an argument. Analysis of a stillbirth cohort did not yield a significant number of cases with biallelic DHCR7 pathogenic variants (PMID: 29433144). A study of pregnancies with the homozygous DHCR7 variant c.964-1G>C (n=32) found intrauterine fetal demise, severe prenatal phenotypes, and death before three months of age (PMID: 32055014). Excess miscarriages were also observed in c.964-1G>C carrier couples (PMIDs: 37301908, 32055014). These observations suggest that homozygosity for DHCR7 c.964-1G>C variant causes severe prenatal phenotypes and can result in early pregnancy loss but additional information is needed to understand the relationship between prenatal phenotypes and other variants in DHCR7. Currently there is no clear relationship of stillbirths in pregnancies with biallelic DHCR7 pathogenic variants. There is also no data currently supporting the relationship between biallelic DHCR7 variants and early miscarriages due to the lack of sequencing data are mostly unavailable.

Nine probands with twelve unique variants (splice, nonsense, missense) reported in seven publications are reported in this curation. Mechanism of pathogenicity is known to be loss-of-function (PMID: 27401223).

Experimental evidence includes three mouse models of disease, rescue experiments showing normalized 7-DCH levels in patient-derived fibroblasts transfected with WT DHCR7, and additional studies demonstrating null or hypomorphic mRNA or protein expression in genes harboring pathogenic variants. Almost all SLOS patients demonstrate intellectual disability (Cunniff et al., 1997; Ryan et al., 1998) and about half meet the DSM-IV criteria for autism diagnosis (Tierney et al., 2000).

In summary, there is definitive evidence to support the relationship between DHCR7 and Smith-Lemli-Opitz syndrome. While the postnatal presentations of this disorder are relatively well understood, and several such features are observed prenatally, more evidence is needed to understand if there is an increased risk for pregnancy loss in affected pregnancies. This curation was originally approved by the ClinGen Intellectual Disability and Autism GCEP on September 9, 2018 (SOP 5). It was later evaluated by the Prenatal Gene Curation Expert Panel on August 15, 2023 (SOP 9). As of June 2024, this record underwent administrative updates to update scoring to be consistent with SOP Version 9 and additions to the evidence summary were made discussing the prenatal presentation. One new case was also added to capture the prenatal presentation of this condition (PMID: 28805615), however the original classification of Definitive remains the same.