Edith Cheng

Genetic counseling and screening of consanguineous couples and their offspring: Recommendations of the national society of genetic counselors

The objective of this document is to provide recommendations for genetic counseling and screening for consanguineous couples (related as second cousins or closer) and their offspring with the goals of1. providing preconception reproductive options2. improving pregnancy outcome and identifying reproductive choices3. reducing morbidity and mortality in the 1st years of life, and4. respecting psychosocial and multicultural issues.The recommendations are the opinions of a multicenter working group (the Consanguinity Working Group (CWG)) with expertise in genetic counseling, medical genetics, biochemical genetics, genetic epidemiology, pediatrics, perinatology, and public health genetics, which was convened by the National Society of Genetic Counselors (NSGC). The consensus of the CWG and NSGC reviewers is that beyond a thorough medical family history with follow-up of significant findings, no additional preconception screening is recommended for consanguineous couples. Consanguineous couples should be offered similar genetic screening as suggested for any couple of their ethnic group. During pregnancy, consanguineous couples should be offered maternal–fetal serum marker screening and high-resolution fetal ultrasonography. Newborns should be screened for impaired hearing and detection of treatable inborn errors of metabolism. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.

Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.

Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.

Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders

Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources.

Role of prenatal ultrasonography in women with positive screen for Down syndrome on the basis of maternal serum markers

OBJECTIVE Our purpose was to evaluate the usefulness of prenatal ultrasonography among women with a positive screen for fetal Down syndrome on the basis of three biochemical markers--maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. STUDY DESIGN A total of 395 women underwent prenatal ultrasonography at a single institution after being identified as screen positive (midtrimester risk > or = 1:195) on the basis of triple-marker screening between 15 and 18 weeks. Ultrasonographic findings were compared with the biochemical markers and the eventual fetal outcome for these patients. Ultrasonographic abnormalities that were evaluated included structural defects, nuchal thickening or cystic hygroma, echogenic bowel, cerebral ventricular dilatation, pyelectasis, and shortened femur. RESULTS Among 395 patients, 374 (94.7%) had normal karyotype by genetic amniocentesis (n = 232) or postnatal follow-up (n = 142), 18 (4.5%) proved to have Down syndrome, and three had other karyotypic abnormalities. One or more ultrasonographic abnormalities were found in nine of 18 (50%) with Down syndrome compared to 27 of 377 (7.2%) other fetuses (p < 0.001). Fetuses with abnormal ultrasonography results included three with other chromosome abnormalities and five with nonchromosomal anomalies. An abnormal ultrasonography result increased the risk of Down syndrome by 5.6-fold (25% from 4.5%) and a negative result reduced the risk by 45% (2.5% from 4.5%). The value of ultrasonography is further enhanced when all chromosome abnormalities and nonchromosomal anomalies are considered. CONCLUSION Abnormal ultrasonographic findings increase the risk for Down syndrome, whereas normal findings are less predictive of normalcy. After correction for inaccurate menstrual dates, genetic amniocentesis should be offered in spite of a normal ultrasonography result among women with positive triple screen.

Global Gene Expression in the Human Fetal Testis and Ovary

Abstract This study describes a temporal profile of gene expression from normal human fetal testes and ovaries. Gonads from 34 fetuses between 9 wk and 20 wk of gestation were obtained from the Department of Pathology and the Birth Defects Research Laboratory at the University of Washington. Relative transcript levels were determined using the Affymetrix Human Genome U133A Plus 2.0 arrays. Sex determination occurs in the human gonad at ∼6 wk of gestation with development of the testis driven by expression of SRY. In this study, SRY transcript was present and elevated at 9 wk of gestation in the testis but was absent in the ovary. The transcript levels of other testis-specific factors SOX9 and AMH and the steroidogenic genes CYP17A1, CYP11A1, STAR, and HSD17B3 were all significantly higher in the testis. In contrast, transcripts known to be involved in meiosis, including STRA8, SPO11, SYCP3, TEX11, TEX14, and STAG3, showed highest expression in the fetal ovary beginning at Week 12. These gene expression profiles will be a resource for understanding and defining normal gonad development and provide the opportunity to dissect abnormal development.

Meiotic recombination in human oocytes.

Studies of human trisomies indicate a remarkable relationship between abnormal meiotic recombination and subsequent nondisjunction at maternal meiosis I or II. Specifically, failure to recombine or recombination events located either too near to or too far from the centromere have been linked to the origin of human trisomies. It should be possible to identify these abnormal crossover configurations by using immunofluorescence methodology to directly examine the meiotic recombination process in the human female. Accordingly, we initiated studies of crossover-associated proteins (e.g., MLH1) in human fetal oocytes to analyze their number and distribution on nondisjunction-prone human chromosomes and, more generally, to characterize genome-wide levels of recombination in the human female. Our analyses indicate that the number of MLH1 foci is lower than predicted from genetic linkage analysis, but its localization pattern conforms to that expected for a crossover-associated protein. In studies of individual chromosomes, our observations provide evidence for the presence of “vulnerable” crossover configurations in the fetal oocyte, consistent with the idea that these are subsequently translated into nondisjunctional events in the adult oocyte.

Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative Cases

Skeletal dysplasias are a heterogeneous group of conditions associated with various abnormalities of the skeleton. These conditions are caused by widespread disturbance of bone growth, beginning during the early stages of fetal development and evolving throughout life. Despite recent advances in imaging, fetal skeletal dysplasias are difficult to diagnose in utero due to a number of factors, including the large number of skeletal dysplasias and their phenotypic variability with overlapping features, lack of precise molecular diagnosis for many disorders, lack of a systematic approach, the inability of ultrasonography (US) to provide an integrated view, and variability in the time at which findings manifest in some skeletal dysplasias. US of suspected skeletal dysplasia involves systematic imaging of the long bones, thorax, hands and feet, skull, spine, and pelvis. Assessment of the fetus with three-dimensional US has been shown to improve diagnostic accuracy, since additional phenotypic features not detectable at two-dimensional US may be identified. The radiologist plays a major role in making an accurate diagnosis; however, representatives of other disciplines, including clinicians, molecular biologists, and pathologists, can also provide important diagnostic information.

Osteogenesis imperfecta: mode of delivery and neonatal outcome

Objective To evaluate the pregnancy characteristics, methods of delivery, and neonatal outcomes of fetuses affected by osteogenesis imperfecta. Methods We reviewed medical records of 1016 individuals whose cells were sent to the University of Washington Collagen Diagnostic Laboratory between 1987 and 1994 for confirmation of diagnoses of osteogenesis imperfecta. Information and neonatal records were available for 167 of those pregnancies. From those we identified method(s) of prenatal detection, delivery method, and neonatal complications, including survival and acquisition of new fractures, and related them to type of delivery. Results The cesarean delivery rate was 54%, most of them (53%) for nonvertex presentation and fewer than 15% because of an antenatal diagnoses of osteogenesis imperfecta. There was an unusually high rate of breech presentation at term (37%). In infants with nonlethal forms of osteogenesis imperfecta, 24 of 59 (40%) delivered by cesarean and 17 of 53 (32%) delivered vaginally had new fractures (χ2 = .89; P = .3). Among 55 infants with the most severe form, 24 of 31 delivered by cesarean and 21 of 24 delivered vaginally died within 2 weeks of birth. Conclusion Cesarean delivery did not decrease fracture rates at birth in infants with nonlethal forms of osteogenesis imperfecta nor did it prolong survival for those with lethal forms. Prenatal diagnosis did not influence mode of delivery in most instances. Most cesarean deliveries were done for usual obstetric indications.

EXIT Procedure: Technique and Indications with Prenatal Imaging Parameters for Assessment of Airway Patency

Successful management of fetal conditions in which airway obstruction is anticipated is now possible because of advances in prenatal imaging and the development of innovative techniques to secure the fetal airway before complete separation of the fetus from the maternal circulation. Fetal ultrasonography and fetal magnetic resonance imaging are complementary imaging modalities in the assessment of fetuses with potential airway obstruction. The ex utero intrapartum therapy (EXIT) procedure is used to secure the fetal airway before complete delivery of the fetus. However, successful intrapartum treatment of fetuses who may need prolonged placental support depends on a multidisciplinary assessment in which the benefits of the EXIT procedure for the fetus are weighed against the risk of maternal complications that may occur during prolongation of the intrapartum period to secure the fetal airway. This multidisciplinary approach requires an understanding of the types of lesions in which intrapartum fetal airway access would be beneficial, a knowledge of the prenatal images that would best delineate the anatomic defect and thus help guide the best approach to securing the airway, and consensus and coordination among medical ethicists, radiologists, obstetric anesthesiologists and obstetricians, pediatric surgeons and anesthesiologists, and neonatologists.

An analysis of meiotic pairing in trisomy 21 oocytes using fluorescent in situ hybridization

We report the use of chromosome 21-specific painting probes to analyze early stages of oogenesis in nine trisomy 21 fetuses. The proportion of cells in zygotene and pachytene in the trisomic ovaries ranged from 8 to 70% with a mean of 42% ± 19 while the comparable values of euploid specimens ranged from 34 to 90% with a mean of 65% ± 19. The low proportion of pairing cells may be the basis for the ovarian dysgenesis observed in some trisomy infants. Five percent of trisomic pachytene cells exhibited complete asynapsis which is an order of magnitude higher than that observed in euploid cells. A large fraction of the asynaptic cells were atretic which is consistent with the hypothesis of meiotic pairing as a signal for atresia. In addition, the asynaptic cells exhibited asynapsis of chromosomes other than 21, which we interpret as an interchromosomal effect of trisomy 21.