Preimplantation Genetic Testing for Desired Pregnancy in Case of Parental Balanced Translocation.

There are two main types of chromosomal translocations known as reciprocal translocations and Robertsonian translocations. These chromosomal rearrangements are described as balanced when there is no significant loss of chromosomal material. Most carriers of balanced translocations are phenotypically normal and may not even know they are carriers of a balanced translocation. A parental balanced translocation may become apparent after having a child with congenital anomalies, during genetic testing, or while trying to conceive due to the increased risk of producing embryos with chromosomal imbalances. In vitro fertilization (IVF) in combination with preimplantation genetic testing (PGT) can potentially decrease the rate of miscarriages and increase the chance of a successful pregnancy. This is a case report of a 29-year-old female with a balanced translocation undergoing IVF with PGTstructural rearrangement (SR) and PGT-aneuploidy (A).

How to Approach Direct-to-Consumer Genetic Testing With Your Patients.

Direct-to-consumer genetic testing (DTC-GT) is genetic testing initiated by a consumer through a commercial company without the direct involvement of a physician or genetics professional. DTC-GT companies have developed tests that provide information about one's ancestry, carrier status, and risk to develop certain conditions. As more consumers participate in DTC-GT, primary care providers (PCPs) are at a greater chance to encounter DTC-GT results and conversations in their practice. PCPs often do not have specialized genetics training and may not feel equipped to engage in a discussion about DTC-GT, but they are well-positioned to explore the perceived benefits and limitations of DTC-GT with their patients. Limitations of DTC-GT include risk for false positive or false negative results, risk for unintended information, and risk for privacy invasion. We provide a resource for PCPs to use when approaching the topic of DTC-GT with their patients including how to discuss motivations for pursuing and concerns about DTC-GT, as well as the limitations and implications of this testing. We hope this resource can guide fruitful conversations between PCPs and patients who are looking for support from their trusted physician while considering DTC-GT or interpreting their results.

Genesurance Counseling: Genetic Counselors' Roles and Responsibilities in Regards to Genetic Insurance and Financial Topics.

While traditional components of genetic counseling sessions are well recognized, less is known about insurance and financial discussions. This study sought to examine "genesurance counseling" which we defined as: that portion of a genetic counseling session, whether intentional or non-intentional, that is devoted to the topic of costs and insurance/third party coverage (particularly for genetic testing). Our objective was to assess genetic counselors' practices and perspective related to genesurance counseling. A survey link was sent by e-mail to members of the National Society of Genetic Counselors (approximately 3100 NSGC members). A total of 571 genetic counselors participated in the survey of which 550 identified as clinical genetic counselors. Survey data were used to investigate differences between specialties, impact on patient rapport, changes in practice dynamics, and devotion of clinic time. Overwhelmingly, 99% of participants acknowledged conducting genesurance counseling, 87% believed it to be part of their job description, and 85% viewed it as an important aspect of genetic counseling. On average, respondents estimated they devoted 10% of their session, or 6 min, to genesurance counseling. Of the surveyed participants, 95% reported genesurance counseling as having some form of influence in a patient's decision regarding genetic testing, and 74% stated that genesurance counseling concerns change the practice and dynamic of their clinic. "Genesurance counseling" is not a topic which has been studied to date. Our study highlights the changes in genetic counselors' roles and responsibilities regarding insurance and financial counseling.

Analysis of Reimbursement of Genetic Counseling Services at a Single Institution in a State Requiring Licensure.

Reimbursement for genetic counseling services was examined at a single institution. Patient encounters utilizing the 96040 CPT® code from 7/31/2009 through 7/31/2013 were reviewed. Exclusion criteria included billing records of patients seen by a physician the same day, self-pay, Medicaid, and Medicare patients. Of the 8,630 encounters with a genetic counselor, 582 encounters were eligible for review. Descriptive statistics (i.e., percentage of encounters receiving some level of reimbursement, average reimbursement rate, number of third party payors providing any level of reimbursement, and number of ICD-9 codes receiving any level of reimbursement) depicted reimbursement of the 96040 CPT® code for the encounters analyzed. Statistical analysis found a significant difference in reimbursement between third party payors that do and do not credential genetic counselors (p < .0001). There was no statistically significant difference between reimbursement rates for primary diagnostic ICD-9 codes when compared to primary diagnostic ICD-9 V codes used. Results will provide a useful baseline for local and national comparisons due to the paucity of data regarding CPT® 96040.

A Hutterite condition that mimics Bowen-Conradi syndrome.

Bowen-Conradi syndrome (BCS) is a common autosomal recessive condition in the Hutterite population. In 2012, when BCS clinical testing was not available, we reported two babies believed to have BCS based upon their clinical features. Diagnostic molecular testing is now available for this condition. We describe here a brother born to the parents of one of the infants in our previous report. Although clinically both babies in the 2012 report appeared to have the same condition, this current infant was found to have a normal EMG1 gene sequence, and thus, lacks the Hutterite mutation for BCS. We discuss the importance of molecular testing in the Hutterite population.

Bowen-Conradi Syndrome: a trisomy 18-like autosomal recessive disorder common in Hutterites.

Bowen-Conradi syndrome (BCS) is a common lethal condition amongst infants of Hutterite ancestry. We describe a newborn infant with features of BCS, which may mimic trisomy 18 and other conditions such as cerebro-oculo-facial syndrome (COFS) and CHARGE syndrome. We describe the constellation of clinical findings in BCS. We believe this is the first case of BCS clinically confirmed by molecular testing for mutation in the EMG1 gene.

Congenital nasal pyriform aperture stenosis and ocular albinism co-occurring in a sibship with a maternally-inherited 97 kb Xp22.2 microdeletion.

Congenital Nasal Pyriform Aperture Stenosis (CNPAS) is a rare congenital malformation caused by overgrowth of the maxillary bone. We report on two patients, brothers born 3 and 1½ years apart, both presented at birth with radiographically diagnosed CNPAS. Both siblings also were born with ocular albinism, which is known to have X-linked inheritance. Subsequent genetic testing demonstrated a 97 kb deletion in the p arm of the X chromosome in both siblings and their mother. This deletion encompasses a gene known to cause ocular albinism (GPR143), as well as partial deletion of two other genes, TBL1X and SHROOM2. This is the first reported case of CNPAS in siblings, both males, sharing a maternally inherited Xp22.2 deletion.

Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency.

Fumarase deficiency is a rare autosomal recessive metabolic condition. We report on a sibship with molecularly confirmed fumarase deficiency. Prenatal findings included agenesis of the corpus callosum, ventriculomegaly, and ventriculoseptal defect. The postnatal course was significant for metabolic acidosis ultimately leading to death around 3 weeks of age. Postmortem findings were noted including swollen mitochondria with abnormal cristae on electron microscopy within the liver. Molecular testing revealed a novel whole gene deletion in conjunction with a point mutation. While the point mutation has been previously reported, the detection of a whole gene deletion has not been described to date in an individual with fumarase deficiency.

Bowen-Conradi: a common Hutterite condition that mimics trisomy 18.

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive condition having significant clinical overlap with trisomy 18. Though rare in the general population, it is quite common in the Hutterites of the United States and Canada. The carrier frequency in the Hutterite population is estimated to be one in 10, making BCS one of the most commonly inherited genetic diseases in any human group studied to date. We describe two infant patients who were initially thought to have trisomy 18, but for whom chromosome studies were normal. Additionally, we briefly review the historical background of the Anabaptist Hutterite populations in South Dakota, compare the clinical findings in BCS and trisomy 18 and discuss the importance of genetic counseling for couples of Hutterite descent.

The influential role of genes in obesity.

Obesity risk is amplified in the presence of obese relatives yet does not usually follow classic Mendelian inheritance patterns. A combination of gene mutations, deletions and single nucleotide polymorphisms are all known to contribute to obesity. Most cases are polygenic, the result of multiple genes interacting with a changing environment. Each "obesity gene" only makes a small contribution to phenotype, but collectively, inherited genetic variations play a major role in determining body mass and how the body responds to physical activity and nutrition. While obesity is most commonly associated with polygenic inheritance, there are other instances in which the cause is monogenic or syndromic. Monogenic obesity typically is caused by a single gene mutation with severe obesity as the main symptom. Syndromic obesity, on the other hand, has many characteristics, of which obesity is one symptom.

Three-dimensional ultrasound to detect Apert syndrome and improve patient understanding.

Standard two-dimensional ultrasound has been used to aid prenatal visualization and detection of anomalies for the past 60 years. Three-dimensional ultrasound, introduced in the 1980s, provides the additional capability of examining the in utero environment from a variety of different angles. Use of this technology in conjunction with standard two-dimensional ultrasound can lead to a more thorough evaluation of structural defects and a greater patient understanding of genetic conditions.

Will predicted positive effects of climate change be enough to reverse declines of the regionally Endangered Natterjack toad in Ireland?

The global amphibian crisis is driven by a range of stressors including disease, habitat loss, and environmental contamination. The role of climate change remains poorly studied and is likely to influence environmental suitability, ranges, reproduction, and phenology. This study aimed to characterize the bioclimatic-habitat niche space of the Natterjack toad (Epidalea calamita) throughout its European range and to assess the impact of climate on the toad's environmental suitability and breeding behavior in Ireland, where declines in recent decades have resulted in it being regionally Red-Listed as Endangered. To address these questions, we first identified which climate variables best predict the current bioclimatic niche, fecundity (number of eggs deposit), and phenology. We then used future climate projections for two time periods (2041-2060 and 2061-2080) and two greenhouse gas emission scenarios (RCP 4.5 and RCP 8.5) to predict how the species range, fecundity, and phenology would change. The European range of the species was found to be limited by winter temperatures while its bioclimatic niche varied markedly throughout its range. Species distribution models suggested projected climate change will increase environmental suitability for the species throughout its range, including Ireland, but most notably in Scandinavia and the Baltic. Fecundity in Ireland was greatest during the cool temperatures of spring and after wet winters associated with ephemeral breeding pool availability. Warm, dry summers in the preceding year influenced fecundity the following spring indicative of carryover effects. Initiation of spawning was driven by spring temperatures, not rainfall. Projections suggested future climate change may increase fecundity in Ireland while spawning may commence earlier throughout the 21st century especially under a high greenhouse gas emission scenario (RCP 8.5). Despite recent range contraction and population declines due to habitat deterioration, the Natterjack toad, if subject to a suitable species conservation strategy, has the potential to be a climate change winner, notwithstanding unpredictable habitat and land-use change, sea-level rise inducing coastal erosion, changes in invertebrate prey abundance, and disease.

Genetic and familial factors influencing breast, colon, prostate and lung cancers.

Knowledge of cancer genetics is advancing our biological understanding of breast, colon, prostate and lung cancers. A family history of any one of these four types of cancer can increase an individual's personal risk to also develop a malignancy. For some families, genetic testing, in combination with genetic counseling, can be a helpful way to identify a hereditary cancer predisposition gene or establish a cancer risk management plan. In this paper, we will review the current state of knowledge surrounding genetic factors influencing breast, colon, prostate and lung cancer.

First-trimester genetic diagnosis: a series of six cases.

A first-trimester screen consists of a nuchal translucency (NT) ultrasound measurement as well as maternal serum testing for pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotropin (hCG). An increased nuchal translucency (NT) thickness at 11 to 14 weeks gestational age is a common finding for Down syndrome, Trisomy 18 and cardiac defects. We present a series of six patients, four with NT measurements greater than the 95th centile, and two additional cases where the NT was normal, but maternal serum biochemical markers were unusual. All six of these cases had a chromosome anomaly or another genetic condition: Noonan syndrome, triploidy, Down syndrome, Trisomy 18, Turner syndrome and a rare chromosome abnormality known as Ring 18-Monosomy 18. Our series underlines the fact that it is important to explore other genetic and chromosome abnormalities, in addition to Down syndrome and Trisomy 18, when there is an abnormality on a first-trimester screen.

The first-trimester screen in clinical practice.

The first-trimester screen combines nuchal translucency measurement and serum levels ot PAPP-A and beta-hCG between 11 and 13 weeks gestational age which can be used to calculate the risk of fetal Trisomy 21 and 18. Although these trisomies are the most common conditions detected, recognition of increased risk for several other fetal conditions and maternal complications have also been documented. A common misconception is that requesting this test implies that the patient will automatically terminate an affected fetus. Although termination may be one option, it is not the primary goal of this screen. If this screen results in the discovery of an abnormal fetus, the patient is allowed maximal time for privacy, formulation of a medical management plan, preparation for caring for a child with special needs, personal research and consultation with appropriate pediatric subspecialists. This test also decreases maternal anxiety throughout pregnancy. The American College of Obstetricians and Gynecologists (ACOG) recommends that all women, regardless of maternal age and risk factors, be offered this screening test. This paper addresses how the test is performed, management of abnormal findings, risk factors and detection rates.

Premature ovarian failure: a phenotypic expression of fragile X premutation.

Fragile X syndrome is the most common cause of mental retardation in the male. Historically, fragile X premutation was considered to be phenotypically silent. In recent reports the premutation has been associated with premature ovarian failure and fragile X-associated tremor/ataxia syndrome. This case describes a 24-year-old woman who presented with irregular menstrual cycles secondary to premature ovarian failure. Subsequent genetic analysis confirmed that she has a premutation for fragile X with 70 CGG trinucleotide repeats.

Clinical course of a 20-month-old child diagnosed prenatally with mosaic ring chromosome 18 and monosomy 18.

We report on a 20-month-old male, diagnosed prenatally with de novo mosaic ring chromosome 18 and low level monosomy 18, who also exhibited an inherited and apparently balanced translocation between chromosomes 3 and 6. We believe this to be the first reported case of prenatally diagnosed mosaic ring chromosome 18 and monosomy 18 in which the child was carried to term. Ring chromosomes are associated with an abnormal phenotype that is dependent on the amount of material that is deleted from the p and q arms. This child has a 22.5 Mb deletion of 18q and a 2.8 Mb deletion of 18p as a result of ring formation. Although the large deletion has resulted in some developmental delays and health problems, the child is making more developmental progress than was anticipated prenatally. We present his clinical course and the genetic counseling challenges associated with this case.

Characterization of aquaporin-4 in muscle and muscular dystrophy.

Aquaporins are a growing family of transmembrane proteins that transport water and, in some cases, glycerol and urea across cellular membranes. Aquaporin-4 (AQP4) is enriched at the sarcolemma of skeletal muscle and may play a role in accommodating the rapid changes in cell volume and hydrostatic forces that occur during contraction in order to prevent damage to the sarcolemma. Recent evidence has shown that AQP4 is absent in dystrophin-deficient mdx mice, suggesting that AQP4 associates with dystrophin and has a role in the dystrophic process. To examine the relationship between aquaporins and muscle disease, and between aquaporins and dystrophin, we have investigated aquaporin expression in various mouse models of muscular dystrophy and cardiomyopathy before and after the onset of pathology. We find that AQP4 is expressed in prenecrotic mdx muscle despite the absence of dystrophin and that AQP4 is lost after the onset of muscle degeneration. Analysis of various dystrophin transgenic mice reveals that AQP4 is lost even when the dystrophin-glycoprotein complex is present, suggesting that loss of AQP4 is not directly resulting from loss of the DGC. AQP4 was also lost in muscular dystrophies caused by primary mutations in the sarcoglycan genes. Taken together, our data demonstrate that AQP4 loss in skeletal muscle correlates with muscular dystrophy and is a common feature of pathogenesis.

Solving the puzzle: case examples of array comparative genomic hybridization as a tool to end the diagnostic odyssey.

We review 3 cases where array comparative genomic hybridization made a difference in the medical management of the patient, ended the diagnostic odyssey, predicted prognosis for the patient, and/or provided closure to the family. Comparative genomic hybridization is a useful tool for testing individuals with clinical examinations suggestive of a genetic syndrome but in which a specific syndrome may be difficult to pinpoint. The cost is similar to that of a standard karyotype but there is a higher yield in children and adults with clinical signs of a genetic syndrome.

Blepharophimosis-ptosis-epicanthus inversus syndrome and hypergonadotropic hypogonadism.

OBJECTIVE: To describe a woman with blepharophimosis-ptosis-epicanthus inversus syndrome and hypergonadotropic hypogonadism. DESIGN: Case report. SETTING: University medical center. PATIENT(S): One 25-year-old woman. INTERVENTION(S): Pedigree, hormone assays, and donor embryo transfer. MAIN OUTCOME MEASURE(S): Pregnancy. RESULT(S): The patient with hypergonadtropic hypogonadism obtained an ongoing pregnancy after donor embryo transfer. CONCLUSION(S): Blepharophimosis-ptosis-epicanthus inversus syndrome is associated with evidence of premature ovarian failure. The syndrome is a sex-limited, autosomal dominant trait that causes selective loss of ovarian function in affected females. This report emphasizes the importance of a thorough family history and pedigree analysis in the evaluation of a patient with hypergonadotropic hypogonadism.