The Recurrent t(11;22)(q23;q11.2) Can Occur as a Post-Zygotic Event.

The AT-rich repeat on chromosome 22q11.2 is known to be involved in the recurrent constitutional t(11;22)(q23;q11.2). Segregation of this translocation has been reported in several hundred families, but a de novo translocation event has been identified in only 8 cases, and everytime the translocation originated in paternal germ-line chromosomes. Further, de novo t(11;22) rearrangements have been detected in the sperm of healthy males, leading to the hypothesis that it occurs somewhere along the meiosis-spermatogenesis pathway. This report describes a woman whose constitutional karyotype revealed mosaicism for the recurrent t(11;22) and the subsequent testing performed to determine the origin of the translocation event. Karyotype analysis, translocation-specific PCR, human identity testing, and a SNP genotyping array were performed to detect mosaicism and/or chimerism. As a result, the SNP genotyping array revealed no evidence for mosaicism in genomic DNA beyond mosaicism for the balanced t(11;22). Human identity testing and the SNP genotyping array ruled out chimerism. PCR of the translocation breakpoint followed by sequencing confirmed that the translocation had occurred at the typical t(11;22) breakpoints. In conclusion, these results indicate that the translocation occurred post-fertilization, providing the first evidence of a de novo t(11;22)(q23;q11.2) occurring in a maternal mitotic environment.

The benefits and limitations of cell-free DNA screening for 22q11.2 deletion syndrome.

Cell-free DNA testing is increasingly being used to screen pregnant women for fetal aneuploidy. This technology may also identify microdeletion syndromes, including 22q11.2 deletion syndrome, the most common microdeletion syndrome, and the 22q11.2 duplication syndrome. The purpose of this paper is to provide an overview of the 22q11.2 deletion syndrome, to review the early experience with cell-free DNA screening for this deletion and to consider the potential benefits that may be associated with prenatal detection of the deletion. © 2016 John Wiley & Sons, Ltd.

Cell-free DNA screening and sex chromosome aneuploidies.

Cell-free DNA (cfDNA) testing is increasingly being used to screen pregnant women for fetal aneuploidies. This technology may also identify fetal sex and can be used to screen for sex chromosome aneuploidies (SCAs). Physicians offering this screening will need to be prepared to offer comprehensive prenatal counseling about these disorders to an increasing number of patients. The purpose of this article is to consider the source of information to use for counseling, factors in parental decision-making, and the performance characteristics of cfDNA testing in screening for SCAs. Discordance between ultrasound examination and cfDNA results regarding fetal sex is also discussed.

Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.

Beare-Stevenson syndrome (BSS) is a rare FGFR2-associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes. BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy. There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype. Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2. Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome. Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth. Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care. One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death. Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy. Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea. This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise.

CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops.

BACKGROUND: Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS. METHODS: Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes. RESULTS: Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known 'cholestasis genes' did not demonstrate homozygosity in the LCS patient. CONCLUSIONS: Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.

Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy?

Testing cell-free DNA (cfDNA) in maternal blood samples has been shown to have very high sensitivity for the detection of fetal aneuploidy with very low false-positive results in high-risk patients who undergo invasive prenatal diagnosis. Recent observation in clinical practice of several cases of positive cfDNA tests for trisomy 18 and trisomy 13, which were not confirmed by cytogenetic testing of the pregnancy, may reflect a limitation of the positive predictive value of this quantitative testing, particularly when it is used to detect rare aneuploidies. Analysis of a larger number of false-positive cases is needed to evaluate whether these observations reflect the positive predictive value that should be expected. Infrequently, mechanisms (such as low percentage mosaicism or confined placental mosaicism) might also lead to positive cfDNA testing that is not concordant with standard prenatal cytogenetic diagnosis. The need to explore these and other possible causes of false-positive cfDNA testing is exemplified by 2 of these cases. Additional evaluation of cfDNA testing in clinical practice and a mechanism for the systematic reporting of false-positive and false-negative cases will be important before this test is offered widely to the general population of low-risk obstetric patients. In the meantime, incorporating information about the positive predictive value in pretest counseling and in clinical laboratory reports is recommended. These experiences reinforce the importance of offering invasive testing to confirm cfDNA results before parental decision-making.

Genetic screening in reproductive health care.

Genetic screening is used to identify individuals who have genetic variations or mutations that are associated with a particular disorder. Genetic screening may be useful to plan for periodic evaluation, implementation of preventive strategies, or initiation of therapeutic interventions. Current practice is to offer carrier screening for certain genetic diseases during the preconception encounter or more commonly as part of early prenatal care.

Incorporating first-trimester Down syndrome studies into prenatal screening: executive summary of the National Institute of Child Health and Human Development workshop.

The National Institute of Child Health and Human Development (NICHD), the Society for Maternal-Fetal Medicine, and the American College of Obstetricians and Gynecologists (ACOG), cosponsored a workshop on December 16-17, 2004, to discuss the evidence for first-trimester Down syndrome screening and to explore the effects of combining first- and second-trimester screening, given the results of recent U.S. trials. The experts evaluated the evidence for offering first-trimester screening to provide individual risk assessment for Down syndrome. First-trimester screening has been demonstrated to provide efficient Down syndrome risk assessment, with a detection rate of 84% (95% confidence interval 80-87%), which is clinically comparable to the second-trimester quadruple screen at a fixed false-positive rate of 5%. The participants at the workshop concluded that at this time there is sufficient evidence to support implementing first-trimester Down syndrome risk assessment in obstetric practice in the United States, provided that certain requirements can be met. These requirements include training and quality control standards for first-trimester nuchal translucency measurement and laboratory assays, access to chorionic villus sampling, and appropriate counseling regarding screening options.

Impact of self-reported familiarity with guidelines for cystic fibrosis carrier screening.

OBJECTIVE: To assess the impact of self-reported familiarity with published guidelines on knowledge, implementation, and opinions of obstetrician-gynecologists regarding carrier screening for cystic fibrosis. METHODS: A questionnaire pertaining to cystic fibrosis screening guidelines was mailed to 1,165 members of the American College of Obstetricians and Gynecologists. RESULTS: Sixty-four percent of questionnaires were returned. Statistical analyses were limited to the 632 respondents whose primary medical specialty was gynecology (GynOnly) or obstetrics and gynecology (ObGyns). More ObGyns had thoroughly read or skimmed the guidelines (67.1%) than had GynOnlys (41.6%). Correctly responding to basic questions regarding cystic fibrosis was associated with having read the guidelines, although responding to a more complex question was not. Familiarity with the guidelines was associated with correctly identifying the recommendations for offering screening, with practice implementation of cystic fibrosis screening, and with self-ratings of qualifications and training to offer screening and to provide counseling. In contrast, familiarity with the guidelines was not associated with ObGyn's opinion that burden of disease is likely to be influential in patient acceptance of screening. Physicians who had thoroughly read the guidelines were more likely to disagree that the cystic fibrosis screening test is too inaccurate to risk influencing reproductive decision making (thoroughly read = 79% disagree, skimmed = 69%, not read = 58%, not heard of it = 50%). CONCLUSION: There was a strong association between self-reported familiarity with the American College of Obstetricians and Gynecologists/American College of Medical Genetics guidelines and physicians' knowledge, implementation, and ratings of training for offering cystic fibrosis carrier screening.

Practice patterns of obstetrician-gynecologists regarding preconception and prenatal screening for cystic fibrosis.

OBJECTIVE: To assess practices of obstetrician-gynecologists regarding carrier screening for cystic fibrosis (CF). METHODS: A questionnaire investigating practice patterns and opinions pertaining to CF screening was mailed to 1165 members of the American College of Obstetricians and Gynecologists (ACOG), of whom 565 participate in the Collaborative Ambulatory Research Network (CARN) and 600 were randomly selected. RESULTS: Of the questionnaires, 64% were returned. Statistical analyses were limited to the 632 respondents whose primary medical specialty was gynecology (Gyn Only) or obstetrics and gynecology (ObGyn). CARN membership was not a significant factor on any nondemographic measure. Almost one-half of physicians do not ask nonpregnant patients their family history of CF or provide them with information about CF screening. The majority of ObGyns (88.7%) ask obstetric patients their family history of CF, and offer CF carrier screening. Almost two-thirds (65.8%) offer screening to all prenatal patients. Among those ObGyns who selectively offer CF screening to pregnant patients, only 27.4% utilized all of the selection criteria in the guidelines. Liability for not offering screening, familiarity with CF, and the ability to interpret a positive screening test were important physician concerns. CONCLUSION: The results indicate a need for minimizing the complexity of clinical guidelines for population-based genetic screening, prospective assessment of implementation and focused continuing education for providers.

Screening for aneuploidy in twin pregnancies: maternal age- and race-specific risk assessment between 9-14 weeks.

The aim of this study was to calculate the risk for aneuploidy in twin pregnancies between 9-14 weeks utilizing maternal age, race and dizygotic twinning rates. Using previously published risks for aneuploidy in singletons and twins at the time of amniocentesis and at term, we calculated new risk estimates for twins at 9-14 weeks gestation or at the time of chorionic villus sampling. Using these tables, the risk for trisomy 21 in at least one fetus of a twin gestation in a 32-year-old at 9-14 weeks is 1/285 for Whites and for African-Americans. This is equivalent to the risk for trisomy 21 (1/265) in a 35-year-old woman with a singleton at the same gestational age. The risks for trisomies 18 and 13 also follow similar trends. In counseling women with twin pregnancies at the time of first trimester nuchal translucency screening or chorionic villus sampling, it should be noted that the maternal age-related risk for aneuploidy for a 32-year-old is equivalent to that of a 35-year-old woman with a singleton gestation.

Omodysplasia: an affected mother and son.

We describe a second family with mother to son transmission of omodysplasia, a rare skeletal dysplasia characterized by shortened humeri, shortened first metacarpals and craniofacial dysmorphism. The mother in this family had been diagnosed previously with Robinow syndrome; subsequently, her diagnosis was reclassified. Her pregnancy was closely monitored antenatally with serial ultrasound examinations. Delayed ossification of the humerus was noted prenatally. Her son had ambiguous genitalia and similar skeletal manifestations as his mother. A comparison to other known and suspected cases of dominant omodysplasia is presented. Our observations confirm the existence of a dominant variant of omodysplasia, document genital hypoplasia as an important feature of this syndrome in males and highlight the need to differentiate this entity from Robinow syndrome.