DHCR7 – Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive congenital malformation and neurodevelopmental disorder caused by biallelic loss-of-function variants in DHCR7, the gene encoding 7-dehydrocholesterol reductase (DHCR7). Affected individuals present with microcephaly, intellectual disability, dysmorphic facial features, 2–3 toe syndactyly, and variable congenital anomalies, often with elevated 7-dehydrocholesterol and low cholesterol levels.

1 Assess Clinical Validity

The association between DHCR7 and SLOS is Definitive based on >350 unrelated probands with SLOS phenotypes, multi-family segregation, and concordant functional data. Over 80 unique DHCR7 mutations have been identified in multiple cohorts, with consistent biochemical and clinical findings across studies (Definitive; 350 probands [PMID:10677299], 19 affected relatives segregating in families, functional concordance).

2 Summarise Genetic Evidence

SLOS follows an autosomal recessive inheritance pattern. Segregation studies report at least 19 additional affected relatives carrying pathogenic DHCR7 alleles. Case series include >350 probands harboring missense (e.g., p.Tyr280Cys, p.Phe284Leu), splice (c.964-1G>C), and null variants (c.453G>A (p.Trp151Ter)) with recurrent founder alleles across populations ([PMID:11078571], [PMID:10677299]). Carrier frequencies vary by ethnicity, and prenatal diagnosis by biochemical or molecular testing is feasible.

3 Summarise Functional / Experimental Evidence

The pathogenic mechanism is loss of DHCR7 enzymatic activity leading to impaired cholesterol synthesis and accumulation of 7-dehydrocholesterol. In vitro assays demonstrate markedly reduced DHCR7 activity in patient fibroblasts ([PMID:15464432]), and Dhcr7-null mouse models recapitulate human SLOS features. Rescue of cellular cholesterol synthesis by simvastatin induction and cholesterol supplementation further supports the causal role of DHCR7 deficiency.

4 Address Conflicting Evidence

No credible conflicting studies have disputed the role of DHCR7 in SLOS. All reports consistently link biallelic DHCR7 variants to the SLOS phenotype.

5 Integrate & Conclude

Biallelic DHCR7 variants result in deficient conversion of 7-dehydrocholesterol to cholesterol, causing multiple congenital anomalies and neurodevelopmental impairment characteristic of SLOS. Genetic testing of DHCR7 informs diagnosis, enables prenatal counseling, and guides therapeutic interventions such as cholesterol supplementation. Key Take-home: DHCR7 variant analysis is essential for definitive diagnosis and management of SLOS, supporting both clinical decision-making and genetic counseling.

References

• American journal of medical genetics • 1994 • Smith-Lemli-Opitz syndrome in a female with a de novo, balanced translocation involving 7q32: probable disruption of an SLOS gene. PMID:8209918
• American journal of human genetics • 2000 • Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. PMID:10677299
• American journal of medical genetics • 2000 • Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. PMID:11078571
• Molecular genetics and metabolism • 2004 • Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith-Lemli-Opitz syndrome. PMID:15464432

Evidence Based Scoring (AI generated)