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.¹³

TESTING BENEFITS & INDICATIONS
Testing should be considered for those known or suspected to have SLOS, carrier screening, testing for known familial mutations, and at-risk pregnancies. Gene sequence analysis is more accurate than biochemical analysis, as plasma sterol levels and serum cholesterol levels cannot identify mutation carriers⁷ and about 10% of patients with SLOS have normal levels at any age^1,2  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.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: Send 20 µg in TE at 50-100 ng/µl.  Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

REFERENCES
¹Porter FD. Eur J Hum Genet. 2008;16(5):535-541.
²Kelley RI & Hennekam RCM. J Med Genet. 2000;37:321-335.
³Mueller C, Patel S, Irons M et al. Am J Med Genet A. 2003;123:100-106.
⁴Curry CJR, Carey JC, Holland JS et al. Am J Med Genet. 1987;26:45-57.
⁵Tierney E, Nwokoro NA, Porter FD et al. Am J Med Genet. 2001;98:191-200.
⁶Nowaczyk MJM, Whelan MD, Heska T, et al. CMAJ. 1999;161:165-170.
⁷Kelley RI Am J Hum Genet. 1998;63:322-326.
⁸Nowaczyk MJ, Waye JS, Douketis JD. Am J Med Genet A. 2006;140:2057-2062.
⁹Nowaczyk MJ, Zeeman S, Waye JS et al. J Pediatr. 2004;145:530-535.
¹⁰Moebius FF, Fitzky BU, Lee JN et al. Proc Natl Acad Sci USA. 1998;95:1899-1902.
¹¹Tint GS, Salen G, Batta AK et al. J Pediatr. 1995;127:82-87.
¹²Johnson VP. Z Kinderheilkd. 1975;119:221-234.
¹³Cunniff C, Kratz LE, Moser A et al. Am J Med Genet. 1997;68:263-269.
¹⁴Witsch-Baumgartner M, Loffler J, Utermann G. Hum Mutat. 2001;17(3):172-182.

DISCLAIMER
This test was developed and its performance characteristics were determined by Ambry Genetics Corporation.  The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing.  The Ambry Test: Smith-Lemli-Opitz Syndrome analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions and small indels.  It is not intended to analyze the following types of mutations: gross deletions/duplications, gross rearrangements, deep intronic variations, and other unknown abnormalities.  The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated.  A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group.  The Ambry Test: Smith-Lemli-Opitz Syndrome is designed and validated to be capable of detecting >99% of described mutations in DHCR7 (considering less than 1% to be the other types of mutations), which identifies about 96% of one or both mutations causing Smith-Lemli-Opitz Syndrome (SLOS). Smith-Lemli-Opitz Syndrome is a complex clinical disorder, which in most cases is due to alterations in DHCR7 generally detected by the Ambry Test: Smith-Lemli-Opitz Syndrome except as noted above.  Mutations in other genes or the regions not tested by the Ambry Test: Smith-Lemli-Opitz Syndrome can also give rise to clinical conditions similar to Smith-Lemli-Opitz Syndrome. Although molecular tests are highly accurate, rare diagnostic errors may occur.  Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, clerical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice.  Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature.