Dianne N. Abuelo

Familial Thoracic Aortic Aneurysms and Dissections Genetic Heterogeneity With a Major Locus Mapping to 5q13-14

Background—Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome. Methods and Results—Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus. Conclusions—A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.

Reviewing the evidence for mycophenolate mofetil as a new teratogen: Case report and review of the literature

Mycophenolate mofetil (MMF) (CellCept®) is an immunosuppressant drug that is teratogenic in rats and rabbits. Reports of malformations in 13 offspring of women exposed to MMF in pregnancy raise concern that MMF is also a human teratogen. We report an additional child with malformations following prenatal exposure to MMF and review the other 13 reports. We identified a Cambodian male born at 31 weeks gestation to a mother who had been treated for lupus nephritis with MMF from before conception to 12 weeks gestational age. He had bilateral moderate‐to‐severe microtia, external auditory canal atresia, bilateral conductive hearing loss, mild microcephaly, and apparently normal development. Among the 14 MMF‐exposed offspring now reported, the underlying maternal conditions were kidney transplantation (7), lupus nephritis (4), liver transplantation (1), heart transplantation (1), and recurrent erythema multiforme (1). All were exposed in early pregnancy. The most distinctive malformation was moderate‐to‐severe microtia or anotia (12), with external auditory canal atresia in 9. Other common craniofacial malformations and minor anomalies included orofacial clefts (7), hypertelorism (3), coloboma (3), and micrognathia (3). Six had cardiovascular malformations, of which three were either conotruncal or aortic arch defects. MMF dose, reported in 12 patients, was <1 g/day in 4 and 1 g or more/day in 8; no correlation between dose and phenotype severity was apparent. While case reports have limited value in identifying human teratogens, the unusual distribution of malformations among the 14 reported exposed offspring identifies a phenotype suggesting that MMF is likely a human teratogen.

Macrocephaly‐Cutis marmorata telangiectatica congenita: A distinct disorder with developmental delay and connective tissue abnormalities

We describe 13 unrelated children with abnormalities of somatic growth, face, brain, and connective tissue including vasculature. Although the condition in these children falls under the general group of disorders known as cutis marmorata telangiectatica congenita (CMTC), the constellation of abnormalities appears to constitute a distinct and easily recognizable phenotype within this general group. In contrast to most children reported with CMTC, children in this subgroup have a high risk for neurologic abnormalities, including developmental delay, mental retardation, megalencephaly, and hydrocephalus. Early recognition of this condition is important for appropriate surveillance for known complications and parental counseling.

Fetal Smith-Lemli-Opitz syndrome can be detected accurately and reliably by measuring amniotic fluid dehydrocholesterols

The Smith–Lemli–Opitz syndrome, characterized by limb, face and organ abnormalities, and mental retardation, is caused by an inherited block in the step of cholesterol biosynthesis in which the Δ7 double bond of 7‐dehydrocholesterol is reduced. It is diagnosed by the presence of markedly elevated levels of 7‐dehydrocholesterol and 8‐dehydrocholesterol in plasma and tissue. We measured amniotic fluid sterols in 15 pregnancies in 13 women who had previously carried an affected fetus. Cholesterol, 7–dehydrocholesterol and 8‐dehydrocholesterol concentrations averaged 18±3, 9·8±2·9 and 5·0±1·7 μg/ml, respectively, in seven pregnancies with an affected fetus or child. In contrast, these levels were 19±3, 0·05±0·01 and <0·005 μg/ml, respectively, in eight increasedrisk pregnancies with normal outcomes and 16±2, 0·07±0·01 and <0·005 μg/ml in normal controls. 7‐dehydrocholesterol concentrations, 2·2–26 and 0·05–0·10 μg/ml in pregnancies with an affected and unaffected fetus, respectively, did not overlap. Thus, abnormally elevated amniotic fluid dehydrocholesterol concentrations are an accurate predictor of fetal Smith–Lemli–Opitz syndrome. A false‐positive or a false‐negative result is highly unlikely.

Limb defects and congenital anomalies of the genitalia in an infant with homozygous α‐thalassemia

We describe an infant with homozygous alpha-thalassemia, genital abnormalities, and terminal transverse limb defects, whose limbs demonstrate evidence of loss of tissue and abnormal morphogenesis. We propose these defects were due to either severe fetal anemia or to vascular occlusion by abnormal erythrocytes, resulting in hypoxia of the developing distal limbs and genitalia.

Adolescents and genetic testing: what do they think about it?

PURPOSEnTo examine adolescents attitudes toward screening for hereditary disorders.nnnMETHODSnA survey was distributed among 672 students in grades 10 to 12 attending a public suburban high school. The first part of the survey consisted of information about three diseases: familial breast cancer, Tay-Sachs disease, and hypercholesterolemia. The second part was a questionnaire developed by the authors, which explored students attitudes toward testing for these diseases. Comparisons between and within groups were performed using X2 analysis.nnnRESULTSnOut of the 672 surveys distributed, 361 were returned (54% response rate). Mean age of participants was 17 +/- 1 years. Most girls (67%) wanted to be tested for familial breast cancer. Girls were significantly more willing than boys to be tested for Tay-Sachs disease (23% vs. 13%, p <.002) and for hypercholesterolemia (54% vs. 39%, p <.001). Girls who had a relative with breast cancer were significantly more willing to be tested than other girls (p <.05). Individuals in the ethnic risk groups for Tay-Sachs disease were significantly more willing to be tested than those not in the ethnic risk groups (p <.001). However, only 33% of those in the ethnic risk groups for Tay-Sachs disease stated that they would either definitely or probably wish to be tested. Students who had a family history of high cholesterol were significantly more willing to be tested than those without a family history (70% vs. 34%, p <.0001). About 81% of the students with a family history of high cholesterol had never been referred for cholesterol testing. Only about 25% of participants stated that their attitude toward genetic testing was affected by concerns that genetic information might be misused by insurance companies/employers.nnnCONCLUSIONSnThe main motivator for genetic testing is having someone in the family affected by the disease in question. Adolescent girls are more willing to be tested for genetic diseases than are boys.

Distal 5q trisomy resulting from an X;5 translocation detected by chromosome painting

We describe the case of a 13-year-old girl with an apparently de novo unbalanced translocation resulting in the presence of additional chromosomal material on the short arm of one X chromosome, which was detected by conventional G-banding studies. Fluorescence in situ hybridization (FISH) using the Chromoprobe Multiprobe-M protocol confirmed that the additional chromosomal material originated from chromosome 5. The karyotype of this patient is now established to be 46,X,der(X) t(X;5)(p22.3;q33), with a deletion of Xp22.3-pter and partial trisomy of 5q33-qter. The distal 5q trisomy genotype has been associated with clinical signs that include growth and mental retardation, eczema, craniofacial anomalies, and malformations of heart, lungs, abdomen, limbs, and genitalia. Our patient also has short stature, a prominent nasal bridge, a flat philtrum, a thin upper lip, dental caries, and limb and cardiac malformations, but she appears to be mildly affected compared with previously reported cases. This is the first case of distal 5q trisomy arising from a translocation with the X chromosome. Replication studies on this patient show that the derivative t(X;5) chromosome is late replicating in almost all cells examined, which indicates that this chromosome is preferentially inactivated. However, the translocated segment of chromosome 5 appears to be early replicating, which implies that the trisomic 5q segment is transcriptionally active. We cannot determine from these studies whether all or only some genes in this segment are expressed, but this patients relatively mild clinical signs suggest that the critical region(s) that contribute to the distal 5q trisomy phenotype are at least partly suppressed. A review of other patients with X-chromosome translocations indicates that many but not all of them also have attenuated phenotypes. The mechanism of inactivation of autosomal material attached to the X chromosome is complex, with varying effects on the phenotype of the patients that depend on the nature of the autosomal chromatin. Replication studies are of limited utility in predicting expression of autosomal genes involved in X-chromosome translocations. Am. J. Med. Genet. 94:392–399, 2000.

A novel familial 11p15.4 microduplication associated with intellectual disability, dysmorphic features, and obesity with involvement of the ZNF214 gene

We evaluated a patient with mild intellectual disability, obesity, overgrowth, and dysmorphic features. Array comparative genomic hybridization (aCGH) analysis showed a single copy number increase of a BAC clone in the 11p15.4 region. Oligonucleotide aCGH refined the duplication to approximately 2.29u2009megabases (Mb) in size. Testing the parents revealed that the father, who had learning disabilities and overgrowth, also had the 11p15.4 duplication, and the mother had a normal microarray. In addition, the patients brother and grandmother all share clinical features with the proband and tested positive for the duplication. The duplicated region (Chr11:6,934,067‐9,220,605) encompasses 29 genes, including the ZNF214 gene, which has been postulated to play a role in Beckwith–Wiedemann syndrome [Alders et al., 2000 ]. This three‐generation pedigree outlines features of a novel microduplication syndrome.

Smith-Magenis syndrome (interstitial deletion of chromosome 17p) and congenital heart disease

A syndrome with characteristic facial and skeletal features resulting from a specific deletion of material on the short arm of chromosome 17 was first described by Smith et al in 1982. 1 The common findings are brachycephaly, hypoplasia of the middle face, and short broad hands associated with mental retardation. More than 50 cases have been reported, and about one third have congenital heart disease. We report here a patient with atrial and ventricular septal defects together with pulmonary valvar stenosis.

Risk assessment models in genetics clinic for array comparative genomic hybridization: Clinical information can be used to predict the likelihood of an abnormal result in patients

Array comparative genomic hybridization (aCGH) testing can diagnose chromosomal microdeletions and duplications too small to be detected by conventional cytogenetic techniques. We need to consider which patients are more likely to receive a diagnosis from aCGH testing versus patients that have lower likelihood and may benefit from broader genome wide scanning. We retrospectively reviewed charts of a population of 200 patients, 117 boys and 83 girls, who underwent aCGH testing in Genetics Clinic at Rhode Island hospital between 1 January/2008 and 31 December 2010. Data collected included sex, age at initial clinical presentation, aCGH result, history of seizures, autism, dysmorphic features, global developmental delay/intellectual disability, hypotonia and failure to thrive. aCGH analysis revealed abnormal results in 34 (17%) and variants of unknown significance in 24 (12%). Patients with three or more clinical diagnoses had a 25.0% incidence of abnormal aCGH findings, while patients with two or fewer clinical diagnoses had a 12.5% incidence of abnormal aCGH findings. Currently, we provide families with a range of 10-30% of a diagnosis with aCGH testing. With increased clinical complexity, patients have an increased probability of having an abnormal aCGH result. With this, we can provide individualized risk estimates for each patient.