SMITH-LEMLI-OPITZ SYNDROME

Smith-Lemli-Opitz Syndrome — a cholesterol biosynthesis disorder with one of the highest carrier frequencies of any rare disease (1-2% in Europeans), where early cholesterol supplementation improves growth, behavior, and developmental outcomes.

Whole genome sequencing identifies all DHCR7 variants — including the common IVS8-1G>C splice variant that accounts for ~30% of European alleles — for accurate carrier screening and early diagnosis in at-risk families.

DHCR7

About this condition

Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of de novo cholesterol biosynthesis caused by pathogenic variants in DHCR7 (7-dehydrocholesterol reductase, chromosome 11q13.4). DHCR7 catalyzes the final step of cholesterol synthesis — the reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. DHCR7 deficiency produces elevated 7-DHC and reduced cholesterol levels in all tissues, disrupting multiple cholesterol-dependent developmental and signaling pathways. SLOS affects approximately 1 in 20,000-60,000 births in European populations, with a carrier frequency of 1-2% — substantially higher than expected from clinical prevalence, suggesting significant prenatal lethality.

SLOS presents with a highly variable clinical spectrum. Severe forms cause multiple congenital anomalies — holoprosencephaly, ambiguous genitalia in 46,XY males, polydactyly, syndactyly of toes 2-3 (Y-shaped syndactyly, nearly pathognomonic), cleft palate, congenital heart defects, and renal malformations. Milder forms present with intellectual disability, behavioral abnormalities (autism spectrum features, self-injurious behavior, sensory hyperreactivity), feeding difficulties, and photosensitivity without major structural malformations. The 2-3 toe syndactyly is present in virtually all affected individuals and is often the first clinical clue.

Treatment with oral cholesterol supplementation (egg yolk, pharmaceutical-grade cholesterol) improves growth, behavior, and socialization in many patients. Cholesterol supplementation does not reverse structural malformations that formed during embryonic development, but can improve postnatal growth and behavioral outcomes — making early diagnosis and treatment initiation important. Antioxidant therapy (vitamin E, simvastatin to reduce toxic 7-DHC levels) is under investigation. Prenatal diagnosis in at-risk families enables immediate postnatal cholesterol supplementation and avoidance of cholesterol-depleting medications.

The 2-3 toe syndactyly ('Y-shaped syndactyly') is present in virtually all SLOS patients and is often the first clinical clue — any child with 2-3 toe syndactyly and developmental delay should have a 7-DHC level checked.

Gene locus: DHCR7 (11q13.4)

SLOS carrier frequency of 1-2% in Europeans is remarkably high for a rare disease. The discrepancy between carrier frequency and clinical prevalence suggests substantial prenatal loss — making carrier identification important for reproductive counseling.

A 1-2% carrier frequency means approximately 1 in 10,000 European couples are both carriers — most never identified before an affected birth

The DHCR7 carrier frequency of 1-2% in European populations is comparable to cystic fibrosis (CFTR) carrier frequency. Yet SLOS is rarely included in standard carrier screening panels, meaning that carrier couples are not identified preconceptionally. Given that severe SLOS causes devastating congenital malformations and that prenatal lethality may account for a significant proportion of affected conceptuses, carrier identification enables informed reproductive planning. Whole genome sequencing identifies DHCR7 carrier status alongside all other carrier screening genes in a single comprehensive evaluation.

Cholesterol supplementation improves behavior and growth — but only if the diagnosis is made and treatment initiated early

Multiple clinical series demonstrate that cholesterol supplementation in SLOS patients improves growth velocity, reduces photosensitivity, improves sleep, and reduces behavioral irritability and self-injurious behavior. These improvements are dependent on early treatment initiation — cholesterol supplementation started in the neonatal period may produce better outcomes than supplementation started after months or years of cholesterol deficiency. Molecular DHCR7 diagnosis in a family with one affected child enables prenatal diagnosis and immediate neonatal cholesterol supplementation for subsequent affected pregnancies.

Smith-Lemli-Opitz Syndrome — a cholesterol biosynthesis disorder with one of the highest carrier frequencies of any rare disease (1-2% in Europeans), where early cholesterol supplementation improves growth, behavior, and developmental outcomes.

Smith-Lemli-Opitz Syndrome

SLOS carrier frequency of 1-2% in Europeans is remarkably high for a rare disease. The discrepancy between carrier frequency and clinical prevalence suggests substantial prenatal loss — making carrier identification important for reproductive counseling.

A 1-2% carrier frequency means approximately 1 in 10,000 European couples are both carriers — most never identified before an affected birth

Cholesterol supplementation improves behavior and growth — but only if the diagnosis is made and treatment initiated early

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