Smith-Lemli-Opitz Syndrome (SLOS)

Smith-Lemli-Opitz syndrome is a highly variable inherited disorder affecting cholesterol metabolism. It causes behavioral and learning problems, as well as a variety of congenital malformations.


Smith-Lemli-Opitz syndrome is a highly variable inherited disorder affecting cholesterol metabolism. It causes behavioral and learning problems, as well as a variety of congenital malformations.

Ambry offers sequencing of the gene that causes Smith-Lemli-Opitz syndrome (SLOS) in order to provide an accurate diagnosis, which enables early treatment that maximizes patient outcome and allows for testing of at-risk family members.

Disease Name 
Smith-Lemli-Opitz Syndrome
Disease Information 

SLOS is one of the most common autosomal recessive disorders in the North American Caucasian population, with an incidence of 1 in 20,000-70,000 and a carrier rate of 1-3% with large differences between ethnic groups.1,2,7,8,9   SLOS is a highly variable disorder of cholesterol metabolism with a broad spectrum of symptoms; these range from moderate behavioral and learning problems to lethal malformations.1 While there are no clear diagnostic criteria for SLOS, the most common clinical characteristics can be found in the table below.

Common clinical characteristics of Smith-Lemli-Opitz syndrome2,3,4,5
Feature Frequency
Intellectual disabilities (varying degrees) 97%
Post-natal growth retardation 85%
2-3 toe syndactyly 97%
postaxial polydactyly 52%
cleft palate 51%
Cardiac defects 50%
Abnormal genital formation (especially hypospadias and ambiguous genitalia in males 20-50%
Autism spectrum disorder 50%
Behavior problems (hyperactivity, sleep abnormalities, irritability, and self-injurious behaviors Variable
Facial features (microcephaly, bitemporal narrowing, ptosis, small chin Variable
Feeding difficulties and gastrointestinal anomalies Variable

Loss-of-function mutations in the DHCR7 gene cause a deficiency of the 7-dehydrocholesterol-reductase enzyme.10 This enzyme is the catalyst for the last step of cholesterol synthesis (the conversion of 7-dehydrocholesterol, or 7-DHC, to cholesterol. The deficiency of this enzyme results in general cholesterol deficiency and accumulation of 7-DHC in all body tissues (see diagram below) in those with SLOS.

The severity of symptoms of SLOS can correlate to the extent of the cholesterol deficiency and the types of mutations an individual has.11 The life expectancy of patients with SLOS varies, with an estimated 27% dying before two years of age.12 This seems to be determined by the severity of internal malformations and quality of treatment, rather than the level of 7-DHC accumulation.1

Special dietary cholesterol supplementation has been shown to help restore growth, alleviate behavior problems and improve general health.6 Additionally, autism spectrum disorder-type behaviors can improve or resolve with treatment, but can return if treatment is stopped.2

Testing Benefits & Indication 

Direct molecular diagnosis by genetic testing remains the most decisive tool, as biochemical tests can be normal in those with SLOS.14 Biochemical testing is also ineffective at detecting carriers of the disease. SLOS testing can be considered:

  • To confirm a suspected diagnosis in a clinically affected individual.  An early diagnosis directly impacts medical management and allows implementation of treatment in a timely manner to optimize care for a patient.
  • For testing other at-risk relatives, including children and prenatal testing for known familial mutations.
Test Description 

Our Smith-Lemli-Opitz syndrome genetic testing includes next generation sequencing (NGS) and deletion/duplication analysis of the DHCR7 gene. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS. Additional Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.13 This test targets detection of DNA sequence mutations in all coding domains, and well into the 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed utilizing a targeted chromosomal microarray.

Mutation Detection Rate 

~96% of patients with clinical characteristics of SLOS will have two detectable mutations in DHCR7 (clinical sensitivity).14,15  Ambry's DHCR7 analysis can detect >99.9% of described mutations in the gene, when present (analytical sensitivity). 

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Prenatal: Prenatal testing is available. 

Turnaround Time 
2180 DHCR7 Gene Sequence Analysis and deletion/duplication 14 - 28 


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  2. Kelley RI and Hennekam RCM. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000 May; 37(5):321-35.
  3. Mueller C, et al. Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease. ,u>Am J Med Genet A. 2003 Nov; 123A(1):100-6.
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  10. Moebius FF, et al. Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci USA.
  11. Tint GS, et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr. 1995 Jul;127(1):82-7.
  12. Johnson VP. Smith-Lemli-Opitz syndrome: review and report of two affected siblings. Z Kinderheilkd. 1975;119(4):221-34.
  13. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.
  14. Witsch-Baumgartner M, et al.  Mutations in the human DHCR7 gene. Hum Mutat. 2001 Mar;17(3):172-82.
  15. DeBarber AE, et al. Smith-Lemli-Opitz syndrome. Expert Rev Mol Med. 2011 Jul 22;13:e24