American Journal of Medical Genetics 125A:173–176 (2004) Rapid Publication Founder Effect for the T93M DHCR7 Mutation in Smith-Lemli-Opitz Syndrome Malgorzata J.M. Nowaczyk, 1,2 * Diana Martin-Garcia, 3 Angel Aquino-Perna, 3 Miguel Rodriguez-Vazquez, 3 Donna McCaughey, 2 Barry Eng, 2 Lisa M. Nakamura, 1 and John S. Waye 1,2 1 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada 2 Hamilton Regional Laboratory Medicine Program, Hamilton, Canada 3 Center of Medical Genetics, Sancti Spiritus, Cuba Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive MCA-MR disorder caus- ed by mutations within the 7-dehydrocholes- terol reductase gene, DHCR7. The diagnosis is based on the biochemical findings of ele- vated plasma 7-dehydrocholesterol (7DHC) levels. It is a panethnic condition with variable mutation frequencies in different populations. Ten Cuban patients and four Canadian patients of Mediterranean ances- try with SLOS are reported herein. All these patients are at the mild end of the clinical spectrum (the highest Kelley-Hennekam severity score was 28 in one patient). All patients had genotypes which were com- pound heterozygous or homozygous for T93M; in all the Mediterranean patients the T93M mutation appeared to be associated with the J haplotype. Another compound heterozygote for T93M was of Ukrainian/ Irish ancestry; in this patient the T93M was associated with a new haplotype designated K. The T93M mutation was initially reported as the most common in a series of patients from Italy. Our identification of a single haplotype associated with the T93M muta- tion in patients whose ancestors originate in the region of the Mediterranean Sea basin suggests a founder effect. ß 2003 Wiley-Liss, Inc. KEY WORDS: Smith-Lemli-Opitz syndro- me; DHCR7; T93M mutation; haplotype; founder effect Smith-Lemli-Opitz syndrome (SLOS) is an auto- somal recessive disorder caused by mutations in the 7-dehydrocholesterol reductase gene (DHCR7). DHCR7 encodes the enzyme 3b-hydroxysterol-D7-reductase (7- dehydrosterol reductase, DHCR7) which catalyses the last step of endogenous cholesterol synthesis [Irons et al., 1993; Tint et al., 1994]. The diagnosis of SLOS is based on the presence of elevated plasma 7-dehydrocho- lesterol (7DHC) levels with or without low plasma cholesterol levels. The clinical picture of SLOS has been recognized for almost 40 years [Smith et al., 1964]. Patients have a characteristic facial phenotype, mental retardation, and variable combinations of external and internal malfor- mations. The range of severity extends from prenatal death with holoprosencephaly or other lethal malforma- tions, to mildly affected patients with normal intelli- gence or minimal intellectual impairment [Kelly, 2000; Kelley and Hennekam, 2000; Nowaczyk and Waye, 2001]. More than 90 different SLOS mutations have been identified in the DHCR7 gene [Moebius et al., 1998; Fitzky et al., 1998; Wassif et al., 1998; Waterham et al., 1998; Yu et al., 2000; Jura et al., 2003]. Three mutations account for 2/3 of SLOS alleles identified in Canadian patients: IVS8-1G > C (40.0%), R404C (16.7%), and T93M (8.3%) [Waye et al., 2002]. Although SLOS is a panethnic condition, the relative frequencies of DHCR7 mutations differ significantly between populations. The IVS8-1G > C mutation, while found in many ethnic groups of European origin, is the most frequent muta- tion in patients of Western European ancestry and least common in Czech and Slovak [Koza ´k et al., 2000] or Polish patients [Witsch-Baumgartner et al., 2001a]. *Correspondence to: Dr. Malgorzata J.M. Nowaczyk, McMaster University Medical Centre, Rm. 3N16, 1200 Main Street West, Hamilton, Ontario, Canada, L8S 4J9. E-mail: nowaczyk@hhsc.ca Received 16 June 2003; Accepted 19 September 2003 DOI 10.1002/ajmg.a.20676 ß 2003 Wiley-Liss, Inc.