Smith-Lemli-Opitz Syndrome (SLOS)

Smith-Lemli-Opitz Syndrome (SLOS) is a highly variable autosomal recessive metabolic disorder and it is one of the most common disorders in the North American Caucasian population.

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Smith-Lemli-Opitz Syndrome (SLOS) is a highly variable autosomal recessive metabolic disorder and it is one of the most common disorders in the North American Caucasian population.

SLOS is caused by loss of function mutations in the DHCR7 gene, which cause a deficiency of 7-dehydrocholesterol-reductase in the last step of cholesterol synthesis. This results in general cholesterol deficiency and accumulation of 7-DHC in all body tissues. Severity of clinical presentation of Smith-Lemli-Opitz Syndrome correlates with extent of the cholesterol deficiency. Those with the milder form may only have low to normal intellectual function while those with the severe form have life threatening congenital malformations of the brain, central nervous system, heart and other gastrointestinal anomalies.

The Ambry Test: SLOS is a full Gene Sequence Analysis of DHCR7. About 96% of patients with Smith-Lemli-Opitz Syndrome will have two detectable mutations.

Disease Name 
Smith-Lemli-Opitz Syndrome, SLO
Disease Information 

Smith Lemli-Opitz syndrome (SLOS) is a highly variable syndrome with a broad spectrum of symptoms ranging from moderate behavioral and learning problems to lethal malformations.1 It 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 Typical symptoms can include: mental retardation (97%), post-natal growth retardation (85%), 2-3 toe syndactyly (97%), postaxial polydactyly (52%), cleft palate (51%), cardiac defects (50%), hypospadias (50%), ambiguous genitalia in 20-25% of males,2,3 and characteristic facial features like microcephaly, bitemporal narrowing, ptosis, short nasal root, antevert nares, and small chin.2 Those with the milder form may only have low normal intellectual function3 while those with the severe form have life threatening congenital malformations of the brain, central nervous system, heart and other gastrointestinal anomalies.4

Patients with SLOS may present in the neonatal/infancy period with feeding problems, commonly leading to nasogastric tube feedings.2 Behaviorally, patients may present with hyperactivity, irritability, sleep cycle disturbances with only two to three hours of sleep a night, self-injurious behavior and autism spectrum behaviors, which is seen about half of patients.2,5 Special dietary cholesterol supplementation has been shown to restore growth, alleviate behavior problems and improve general health.6 In addition, autistic behaviors can improve or resolve with treatment, but will return if treatment is stopped.2

SLOS is caused by loss of function mutations in the DHCR7 gene, which cause a deficiency of 7-dehydrocholesterol-reductase.10 This enzyme is the catalyst for the last step of cholesterol synthesis, the conversion of 7-DHC into cholesterol, and results in general cholesterol deficiency and accumulation of 7-DHC in all body tissues. Severity of clinical presentation of SLOS correlates with extent of the cholesterol deficiency.11 The life expectancy of patients with SLOS varies,with an estimated 27% dying before two years of age,12 and seems to be determined by the severity of internal malformations and quality of treatment rather than the level of 7-DHC accumulation.1

Testing Benefits & Indication 

Testing should be considered for those known or suspected to have SLOS, carrier screening, testing for known familial mutations, and at-risk pregnancies. Early diagnosis of SLOS is has been shown to significantly reduce the incidence of autistic behaviors in one study where dietary cholesterol supplementation initiated before five years of age decreased the number of patients with autistic behaviors from 88% to 22%.5

Test Description 

This Ambry Test is a full gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 3-9 of the DHCR7 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. Specific mutation analysis for individual DHCR7 mutations known to be in the family is also available.

Mutation Detection Rate 

About 96% of patients with SLOS will have two detectable mutations in DHCR7.14 Gene sequence analysis at Ambry Genetics is capable of detecting 99% of these mutations when present.

Specimen Requirements 

Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice. 
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

Billing Codes 
Test Code Technique
2180 DHCR7 Gene Sequence Analysis

 

Turnaround Time 
Technique Days
DHCR7 Gene Sequence Analysis 10-21

 

Specialty 
Genes 
References 

1. Porter FD. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2008;16(5):535-541. [PMID: 18285838]

2. Kelley RI & Hennekam RCM. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000;37:321-335. [PMID: 10807690]

3. Mueller C, Patel S, Irons M et al. Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease. Am J Med Genet A. 2003;123:100-106. [PMID: 14556255]

4. Curry CJR, Carey JC, Holland JS et al. Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet. 1987;26:45-57. [PMID: 3812577]

5. Tierney E, Nwokoro NA, Porter FD et al. Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 2001;98:191-200. [PMID: 11223857]

6. Nowaczyk MJM, Whelan MD, Heska T, et al. Smith-Lemli-Opitz syndrome: a treatable inherited error of metabolism causing mental retardation. CMAJ. 1999;161:165-170. [PMID: 10439827]

7. Kelley RI. RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am J Hum Genet. 1998;63:322-326. [PMID: 9683618]

8. Nowaczyk MJ, Waye JS, Douketis JD. DHCR7 mutation carrier rates and prevalence of the RSH/Smith-Lemli-Opitz syndrome: where are the patients?. Am J Med Genet A. 2006;140:2057-2062. [PMID: 16906538]

9. Nowaczyk MJ, Zeeman S, Waye JS et al. Incidence of Smith-Lemli-Opitz syndrome in Canada: results of three-year population surveillance. J Pediatr. 2004;145:530-535. [PMID: 15480380]

10. Moebius FF, Fitzky BU, Lee JN et al. Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci USA. 1998;95:1899-1902. [PMID: 9465114]
 

11. Tint GS, Salen G, Batta AK et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr. 1995;127:82-87. [PMID: 7608816]

12. Johnson VP. Smith-Lemli-Opitz syndrome: review and report of two affected siblings.  Z Kinderheilkd. 1975;119:221-234. [PMID: 166525]

13. Cunniff C, Kratz LE, Moser A et al. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet. 1997;68:263-269. [PMID: 9024557]

14. Witsch-Baumgartner M, Loffler J, Utermann G. Mutations in the human DHCR7 gene. Hum Mutat. 2001;17(3):172-182. [PMID: 11241839]