Smith-Lemli-Opitz syndrome (SLOS) is an inherited multiple malformation syndrome caused by enzymatic deficiency of 3beta-hydroxysterol-Delta(7)-reductase (DHCR7). SLOS is thought to be most common among European Caucasians, with an incidence of 1 in 20,000 to 1 in 30,000 births. To define the carrier rate and ethnic distribution of SLOS, we screened DNA samples from 2,978 unrelated individuals for the most common SLOS mutation (IVS8-1G-->C). Twenty-four heterozygotes of the IVS8-1G-->C mutation were detected in 2,978 individuals of European Caucasian and Black backgrounds. For European Caucasians, the carrier rate for SLOS may be as high as 1 in 30, suggesting an incidence of 1 in 1,700 to 1 in 13,400. This high number is supported by the recent observation of newborn and prenatal incidence of 1 in 22,000 in the Caucasian population. Ours is the first report of the IVS8-1G-->C mutation in persons of African ancestry. Published 2001 Wiley-Liss, Inc.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive MCA-MR disorder caused by mutations within the 7-dehydrocholesterol reductase gene, DHCR7. The diagnosis is based on the biochemical findings of elevated 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 ancestry 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 compound 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 mutation in patients whose ancestors originate in the region of the Mediterranean Sea basin suggests a founder effect.

Metachromatic leukodystrophy (MLD) is

Hb S/b + -thalassemia due to Hb sickle and a novel deletion of DNase I hypersensitive sites HS3 and HS4 of the b locus control region Sickle cell disease (SCD) is one of the most common genetic disorders worldwide and is associated with episodes of acute pain and progressive multi-organ damage. 1 The most common cause of SCD is homozygosity for the hemoglobin sickle (Hb S) mutation, with a minority of cases due to compound heterozygosity for Hb S and other alleles including b-thalassemia. Loss-of-function point mutations of the b-globin gene that abolish (b 0 ) or reduce (b + ) production of normal b-chains are the most common causes of b-thalassemia, with large deletions or rearrangements accounting for a small minority of b-thalassemia alleles.2,3 While patients with Hb S/b 0 -thalassemia generally have severe SCD, the residual production of normal b-chains in Hb S/b + -thalassemia patients is associated with lower Hb S concentration in erythrocytes and a less severe disease. 4 Here, we report the unusual case of an infant who had a newborn screening profile fully consistent with sickle trait, yet was diagnosed later in childhood with typical Hb S/b + -thalassemia. Molecular testing demonstrated that the child was a compound heterozygote for the Hb S mutation and a partial deletion of the b-globin Locus Control Region (bLCR). The deletion removed two of the five DNase I hypersensitivity (HS) regions, providing valuable insight into the roles of individual HS regions in globin gene switching and expression. The proband is now a 6-year old boy who was born to healthy non-consanguineous parents of Caribbean descent. The pregnancy and delivery were unremarkable with no evidence of perinatal anemia or jaundice. Newborn screening was negative for SCD, with the Hb profile being fully consistent with sickle trait (Hb F 79.1%, Hb A 6.0%, Hb S 4.0%, Hb Bart's 9.1%) ( Figure 1A). The patient enjoyed normal health until five years of age, when he was diagnosed with SCD during an admission for unexplained abdominal pain and enlarged spleen (splenic sequestration). Microcytosis, sickle erythrocytes, Howell-Jolly bodies and target cells were observed on the peripheral blood smear. Hemoglobin analysis using high performance liquid chromatography (HPLC) was suggestive of Hb S/b + -thalassemia (Hb A 19.4%, Hb S 72.7%, and Hb A2 2.6%) ( Figure 1B). Since diagnosis, the patient has been admitted for one vasoocclusive event and had a tonsillectomy for obstructive sleep apnea. Nucleotide sequence analysis of the β-gobin gene revealed that the proband was heterozygous for the Hb S mutation (HBB:c.20A>T) with no other mutations of the b-globin gene. Deletion-specific gap-PCR demonstrated that he was also heterozygous for the rightward 3.7 kb single a-globin gene deletion (−a 3.7 /aa). Sequence analysis of the intact aglobin genes failed to detect any point mutations. As this genotype could not explain the reduced expression of Hb A and the SCD phenotype in the proband, we investigated the possibility of compound heterozygosity f...