Genotype-phenotype characterization in 13 individuals with chromosome Xp11.22 duplications.

We report 13 new individuals with duplications in Xp11.22-p11.23. The index family has one male and two female members in three generations with mild-severe intellectual disability (ID), speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Affected individuals were found to have two small duplications in Xp11.22 at nucleotide position (hg19) 50,112,063-50,456,458 bp (distal) and 53,160,114-53,713,154 bp (proximal). Collectively, these two regions include 14 RefSeq genes, prompting collection of a larger cohort of patients, in an attempt to delineate critical genes associated with the observed phenotype. In total, we have collected data on nine individuals with duplications overlapping the distal duplication region containing SHROOM4 and DGKK and eight individuals overlapping the proximal region including HUWE1. Duplications of HUWE1 have been previously associated with non-syndromic ID. Our data, with previously published reports, suggest that duplications involving SHROOM4 and DGKK may represent a new syndromic X-linked ID critical region associated with mild to severe ID, speech delay +/- dysarthria, attention deficit disorder, precocious puberty, constipation, and motor delay. We frequently observed foot abnormalities, 5th finger clinodactyly, tapering fingers, constipation, and exercise intolerance in patients with duplications of these two genes. Regarding duplications including the proximal region, our observations agree with previous studies, which have found associations with intellectual disability. In addition, expressive language delay, failure to thrive, motor delay, and 5th finger clinodactyly were also frequently observed in patients with the proximal duplication.

Meiotic exchange event within the stalk region of an inverted chromosome 22 results in a recombinant chromosome with duplication of the distal long arm.

Meiotic recombination occurs between homologous euchromatic regions of human chromosomes in early meiosis. However, such exchanges have been thought not to occur in the stalk regions of acrocentric chromosomes. We describe a child whose chromosome analysis suggests that crossovers do occur in homologous stalk regions. The proband, initially seen as a term female infant, was born to a 28-year-old mother. Dysmorphic features included wide metopic sutures, low anterior hairline, hypertelorism, external ear malformations, and cleft lip and palate. Blood chromosomes of the proband and parents were studied by G-banding, Q-banding, R-banding, and silver staining. The infant karyotype showed a sub-metacentric chromosome 22; that of the mother showed a pericentric inversion of chromosome 22. Chromosomes of the father were normal. In the infant, the abnormal chromosome 22 long arm appeared normal, but with additional long arm material attached to the distal short arm. In the mother, the distal long arm of the abnormal chromosome 22 was translocated to the distal short arm. The abnormal chromosome stalk in the child was intermediate in size to the stalk size of the abnormal and normal chromosomes 22 in the mother. Fluorescent in situ hybridization (FISH) analysis using chromosome 22 paint and ARSA gene probe confirmed that the duplicated material in the proband was of chromosome 22 origin; the karyotype interpretation is: 46,XX,rec(22)dup(22q)inv(22)(p13q13.1)mat. This abnormal karyotype is most likely due to a crossover event within the inversion loop during meiosis. The stalk length discrepancy suggests that the crossover site occurred in the stalk region.

Effects of dietary cholesterol on plasma lipoproteins in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome is a condition of impaired cholesterol synthesis that is caused by mutations in DHCR7 encoding 7-dehydrocholesterol-Delta7 reductase. Birth defects and mental retardation are characteristic. Deficient plasma and tissue cholesterol and excess cholesterol precursors 7 and 8 dehydrocholesterol (7DHC and 8DHC) contribute to the pathogenesis. Cholesterol is transported to tissues via lipoproteins. We measured the effect of dietary cholesterol (egg yolk) on plasma lipoproteins to evaluate this potential treatment. We used the enzymatic method to measure total sterols in lipoproteins (n=12) and plasma (n=16). In addition, we analyzed individual plasma sterols by a gas chromatographic method. Samples were evaluated after 3 wk of a cholesterol-free diet and after 6-19 mo of dietary cholesterol. We also analyzed the distribution of sterols in lipoproteins and the apolipoprotein E genotype. Dietary cholesterol significantly increased the total sterols in plasma (2.22 +/- 0.13 to 3.10 +/- 0.22; mean +/- SEM; p < 0.002), in LDL (0.98 +/- 0.13 to 1.52 +/- 0.17 mM), and in HDL (0.72 +/- 0.04 to 0.92 +/- 0.07). Plasma cholesterol increased (1.78 +/- 0.16 to 2.67 +/- 0.25 mM; p < 0.007) and plasma 7DHC decreased in 10 children, but the mean decrease was not significant. The distribution of individual sterols in each lipoprotein fraction was similar to the distribution in plasma. The baseline cholesterol and the response to dietary cholesterol was the same in children with 3/3 and 3/4 apolipoprotein E genotypes. Dietary cholesterol increased total sterols in plasma, LDL, and HDL in children with Smith-Lemli-Opitz syndrome. These favorable increases in the lipoproteins are potentially therapeutic for this condition.