Amyotrophic Lateral Sclerosis Genetic Access Program: Paving the Way for Genetic Characterization of ALS in the Clinic.

OBJECTIVE: To report the frequency of amyotrophic lateral sclerosis (ALS) genetic variants in a nationwide cohort of clinic-based patients with ALS with a family history of ALS (fALS), dementia (dALS), or both ALS and dementia (fALS/dALS). METHODS: A multicenter, prospective cohort of 573 patients with fALS, dALS, or fALS/dALS, underwent genetic testing in the ALS Genetic Access Program (ALS GAP), a clinical program for clinics of the Northeast ALS Consortium. Patients with dALS underwent C9orf72 hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent C9orf72 HRE testing, followed by sequencing of SOD1, FUS, TARDBP, TBK1, and VCP. RESULTS: A pathogenic (P) or likely pathogenic (LP) variant was identified in 171/573 (30%) of program participants. About half of patients with fALS or fALS/dALS (138/301, 45.8%) had either a C9orf72 HRE or a P or LP variant identified in SOD1, FUS, TARDBP, TBK1, or VCP. The use of a targeted, 5-gene sequencing panel resulted in far fewer uncertain test outcomes in familial cases compared with larger panels used in other in clinic-based cohorts. Among dALS cases 11.8% (32/270) were found to have the C9orf72 HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the C9orf72 HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry. CONCLUSIONS: The ALS GAP program provided a genetic diagnosis to ∼1 in 3 participants and may serve as a model for clinical genetic testing in ALS.

6 feet apart but working together.

Prior to COVID-19, the field of genetic counseling was responding to a workforce shortage in patient-facing roles through efforts to increase the training capacity within existing programs, as well as development of new programs. These efforts were hindered by the number and capacity of fieldwork training sites. COVID-19 heightened this barrier with a sudden restriction on student training for an indefinite period of time. The onset of these restrictions highlighted the need to think creatively and, more importantly, collaboratively for ways to not only expand but also maintain fieldwork training capacity. Described here are two different collaborative efforts in response to pandemic-related cancellations of important curriculum components: 1) the development of clinical simulation experiences and coursework shared between two ACGC accredited training programs; and 2) the creation of a virtual laboratory curriculum between an ACGC accredited training program and a non-academic laboratory partner. This Professional Issues paper illustrates how collaboration with our academic and non-academic colleagues benefits students, training programs and non-academic partners beyond the needs of the initial crisis of a global pandemic.

Neuroblastoma in a 17-week fetus: a stimulus for investigation of tumors in a series of 2786 stillbirth and late miscarriages.

Although tumors are an occasional cause of neonatal death and have been reported in stillbirths, there are no studies specifically evaluating the frequency or types of tumors in stillborn infants. We observed metastatic neuroblastoma in a fetus miscarried at 17 weeks of gestational age. Fetal death was attributed to endocrine effects of the tumor causing fetal hypertension, arrhythmia, and/or placental dysfunction. This case, which is the earliest report of a pathologically confirmed neuroblastoma, prompted review of all tumors in the Wisconsin Stillbirth Service Program database. There were 10 lethal and two incidental tumors among the 2,786 stillbirths and second trimester miscarriages in the database for an overall incidence of 1/232, which is about 50 times the incidence of clinically recognized tumors in liveborn infants. The most frequent tumors were teratoma and hemangioma that, while benign, caused death due to high output cardiac failure, hemorrhage into the tumor, or obstruction of vital organs. Only three tumors were malignant, and except for the index case, mechanisms of death were similar to those of the benign tumors. Except for the index case, all were found in the third trimester, suggesting that congenital tumors rarely become lethal until the third trimester. However, it is also possible that tumors may be missed in younger fetuses. The possibility of detecting an unsuspected tumor is yet another reason for autopsy in stillbirths and late miscarriages.

Rodriguez syndrome with SF3B4 mutation: a severe form of Nager syndrome?

We report on the findings of a novel heterozygous de novo SF3B4 mutation in a long-surviving patient with clinical features of Rodriguez syndrome including severe acrofacial dysostosis, phocomelia with pre- and post-axial limb defects, fibular agenesis, rib, and shoulder girdle anomalies. Since SF3B4 mutations have been recently associated with Nager syndrome, this suggests that at least some cases of Rodriguez syndrome are either allelic to or represent unusually severe manifestations of Nager syndrome. Although clinical overlap is obvious, this is somewhat surprising given the presumed autosomal recessive inheritance of Rodriguez syndrome. Investigation of other Rodriguez syndrome patients is needed to clarify the genetic mechanism and possible heterogeneity in patients with clinical features of Rodriguez syndrome.

Stillbirth: the heart of the matter.

We evaluated 2,083 cases within the Wisconsin Stillbirth Service Program (WiSSP) that had autopsy reports or ultrasound data relevant to the heart. Of these, 167/1,782 (9.4%) stillbirths after 20 weeks and 11/301 (3.7%) miscarriages <20 weeks had congenital heart disease (CHD). Cases were classified by type of heart defect and whether it related to cause of death. Among cardiac anomalies that contributed significantly to fetal death, 125/151 (83%) were associated with underlying conditions or syndromes, nearly half of which were chromosomal. The most common forms of CHD in stillborns were severe cyanotic lesions (3%), then ventricular (2.6%) and atrial (1.9%) septal defects. Compared to livebirths, this represents a shift toward more severe cardiac lesions, although all comparable categories, including non-lethal conditions such as atrial septal defect, are more common in stillbirths. Clinical cardiomyopathy was identified as cause of death in 1.2% of stillborns. Cardiomegaly, occurring in 26.7% of all cases and 76.7% of infants born to diabetic mothers, may represent undiagnosed cardiomyopathy and/or may decrease fetal tolerance of hypoxia. In contrast, 78.5% of Turner syndrome infants, all <32 weeks, had small hearts. More attention to cardiac findings can lead to increased understanding of stillbirth causes. Based on our findings, we recommend chromosome studies on all stillbirths and close attention to the heart during second trimester ultrasounds, with chromosome studies offered if CHD is found. Consideration of heart size can result in prenatal identification of infants at risk for stillbirth, particularly large hearts in fetuses of diabetic mothers in the third trimester, which may identify fetal cardiomyopathy before it becomes life-threatening.

Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors.

PURPOSE: To provide practice recommendations for genetic counselors whose clients are considering cystic fibrosis (CF) carrier testing or seeking information regarding CF molecular test results. The goals of these recommendations are to: 1) Provide updated information about the natural history, diagnosis, and treatment of CF and related conditions. 2) Supplement genetic counselors' knowledge and understanding of the available carrier screening and diagnostic testing options. 3) Describe the current state of genotype/phenotype correlations for CFTR mutations and an approach to interpreting both novel and previously described variants. 4) Provide a framework for genetic counselors to assist clients' decision-making regarding CF carrier testing, prenatal diagnosis, and pregnancy management. Disclaimer The practice guidelines of the National Society of Genetic Counselors (NSGC) are developed by members of the NSGC to assist genetic counselors and other health care providers in making decisions about appropriate management of genetic concerns; including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue, and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the NSGC practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are only current as of their publication date, and are subject to change without notice as advances emerge.In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health care provider's best medical judgment based on the clinical circumstances of a particular patient or patient population.Practice guidelines are published by NSGC for educational and informational purposes only, and NSGC does not "approve" or "endorse" any specific methods, practices, or sources of information.

Intestinal ganglioneuromatosis: unusual presentation of Cowden syndrome resulting in delayed diagnosis.

We report on a 25-year-old woman who presented as a teenager with macrocephaly and multiple gastrointestinal lesions including ganglioneuromas, hamartomas, lipomas, juvenile, and hyperplastic polyps in association with extra-intestinal tumors including a retroperitoneal lipoma, storiform collagenoma, and a fibrolipomatous hamartoma. PTEN mutation analysis identified a deletion in exon 2, confirming the diagnosis of Cowden syndrome. While intestinal polyps are common among Cowden patients who undergo endoscopy, and intestinal ganglioneuromas are occasionally reported, they are not usual presenting manifestations. Intestinal ganglioneuromatosis is divided into three subgroups: (1) polypoid ganglioneuromatosis (usually few isolated ganglioneuromas), (2) generalized ganglioneuromatosis (usually associated with NF1 or MEN), and (3) ganglioneuromatous polyposis without known systemic disease, although there are several reported patients with multiple lipomas. This individual with Cowden syndrome closely resembles the latter group, thus we suggest that patients with ganglioneuromatous polyposis, especially in association with lipomas, should be evaluated for possible Cowden syndrome.

Wisconsin Stillbirth Service Program: analysis of large for gestational age cases.

Since its inception in 1983, the Wisconsin Stillbirth Service Program (WiSSP) has reviewed over 2,600 referrals. Among 2,451 with fetal weight and gestational age recorded, 186 (7.6%) were large for gestational age (LGA), which is more than expected. We reviewed these cases to identify factors causing or contributing to fetal death as well as increased fetal size. LGA losses tended to occur later in pregnancy than non-LGA losses. The most common cause of death in LGA fetuses was fetal (43.5%), followed by placental (22.6%), and maternal (11.2%), which contrasts with previous studies involving the same database, but unselected for fetal weight, in which 21.5%, 40.0%, and 12.7% had fetal, placental, and maternal causes, respectively. The most common fetal cause was hydrops (60 cases/32.4%), which was most frequently idiopathic (16/26.6%), followed by cardiac (11/18.3%), Turner syndrome (8/13.3%), and twin-twin transfusions (6/10.0%). Placental causes, most commonly abruption and infarct, were more frequent in diabetic mothers, accounting for 33% versus only 18% in the entire LGA group. In the LGA group overall, 21% of mothers were diabetic, and most stillbirths in diabetic mothers occurred after 28 weeks. Despite large placentas (>95th centile) in 71.8% of the LGA cohort compared to 11% previously reported in the entire database, the most extreme LGA cases had a high fetoplacental ratio. We recommend pathologic evaluation of placentas from all stillbirths, close follow-up of pregnancies complicated by diabetes, and continued research into causes and pathophysiology of hydrops.

Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening.

Newborn screening is a public health policy program involving the centralized testing laboratory, infant and their family, primary care provider, and subspecialist for confirmatory testing and follow-up of abnormal results. Cystic fibrosis (CF) newborn screening has now been enacted in all 50 states and the District of Columbia and throughout many countries in the world. Although CF neonatal screening will identify the vast majority of infants with CF, there are many factors in the newborn screening system that can lead to a missed diagnosis of CF. To inform clinicians, this article summarizes the CF newborn screening system and highlights 14 factors that can account for a missed diagnosis of CF. Care providers should maintain a high suspicion for CF if there are compatible symptoms, regardless of the results of the newborn screening test. These factors in newborn screening programs leading to a missed diagnosis of CF present opportunities for quality improvement in specimen collection, laboratory analysis of immunoreactive tryspinogen (IRT) and CF mutation testing, communication, and sweat testing.

Mild Tessier No. 7 cleft with PHACE syndrome: the case for pulmonary vascular steal.

We describe an unusual case of PHACE syndrome that provides a demonstration of the role of vascular anomalies in the causation of external ear and facial anomalies. The child in our case was characterized by a small segmental hemangioma of the face, tetralogy of Fallot, and anomalous origin of left common carotid artery from pulmonary artery with retrograde blood flow. This presumably resulted in hypoperfusion of the left side of the face resulting in a Tessier number 7 cleft and left ear anomaly explained by pulmonary vascular steal phenomenon. The absence of posterior fossa anomalies may reflect normal perfusion via the Circle of Willis.

Wisconsin stillbirth services program: a multifocal approach to stillbirth analysis.

Stillbirth accounts for about 26,000 deaths annually in the US. In most previous studies, discrete causes are identified in less than half of all stillbirths. In order to identify causes and non-causal but potentially contributing abnormalities, we analyzed 416 of the most recent (2004-2010) Wisconsin Stillbirth Service Program (WiSSP) cases from a multifocal approach. In 70% of cases a cause sufficient to independently explain the demise was identified including 40% placental, 21.5% fetal, and 12.7% maternal. Results for stillbirths and second trimester miscarriages did not differ significantly. In 95% of cases at least one cause or non-causal abnormality was recognizable, and in two-thirds of cases, more than one cause or non-causal abnormality was identified. In cases with maternal cause, the placenta was virtually always abnormal. Both placentas (59%) and fetuses (38%) were frequently smaller than expected for gestational age. Previous miscarriage and/or stillbirth were risk factors for second and third trimester losses, with 35% of previous pregnancies ending in fetal demise. Recommendations include complete evaluation of all second and third trimester losses with special attention to placental pathology and thorough investigation for multiple causes or abnormalities whether or not a primary cause is initially recognized. Improved understanding of the causes of late miscarriage and stillbirth may contribute to recognition and management of pregnancies at risk and eventually to prevention of stillbirth.

Extreme values of maternal serum analytes in second trimester screening: looking beyond trisomy and NTD's.

Second trimester maternal serum screening can identify high risk pregnancies and fetuses at risk for birth defects (in addition to those in the standard interpretation). The purpose of this study was to quantify such risks to improve counseling. We compared outcomes of 692 pregnancies that had abnormal levels of at least one analyte with a cohort of 713 pregnancies with normal analytes. Increased risks include: demise with high AFP and low uE3; intrauterine growth restriction with high AFP, high and low hCG, and low uE3; placental abnormalities with high AFP; fetal stress with high AFP and high hCG. Birth defects are increased with high AFP, high hCG, and low hCG. When two or more analytes are abnormal, 46% have a poor outcome. Abnormal levels of maternal serum analytes provide information in addition to the risks for neural tube defects, Down syndrome, and trisomy 18. This information is important for counseling and pregnancy management.

A tailored approach to family-centered genetic counseling for cystic fibrosis newborn screening: the Wisconsin model.

This article describes the development of a tailored family-centered approach to genetic counseling following abnormal newborn screening (NBS) for cystic fibrosis (CF). A genetic counseling consortium reviewed research literature, selected theoretical frameworks, and incorporated counseling psychology micro skills. This innovative intervention integrated theories and empirically validated techniques. Pilot testing and parent feedback confirmed satisfaction with and feasibility of the approach designed to (a) minimize parents' distress, (b) facilitate parents' understanding, (c) increase parents' capacities to use genetic information, and (d) enhance parents' experiences with genetic counseling. Counselors engage in a highly interactive process of evaluating parents' needs and tailoring assessments and interventions that include a therapeutic environment, the family's emotional needs, parents' informational needs, and a follow-up plan. This promising new model is the first to establish a theory-driven, evidence-based standard for genetic counseling in the context of NBS for CF. Additional research will evaluate the model's efficacy in clinical practice.

Patient and family experiences and opinions on adding 22q11 deletion syndrome to the newborn screen.

22q11 deletion syndrome (22qDS) has recently been proposed for addition to the newborn screening panel in Wisconsin and it seems likely that it may soon be considered in other states as well. Input from patients with 22qDS and their family was gathered from 21 phone interviews. Cardiac, palate, hypocalcemia, and multiple anomalies were common reasons for involved patients to be diagnosed, though age at diagnosis ranged from birth to adulthood. Many commented on their struggles with 22qDS, including worries about the future and the patient's independence. In general, respondents favored newborn screening for 22qDS because it would help prevent some medical problems, increase access to services, explain existing problems, and identify mild cases. However, a minority expressed reservations, including concerns that it would disrupt bonding, could be too costly, and would not be useful for mild cases.

Newborn screening programs: should 22q11 deletion syndrome be added?

The highly variable 22q11 deletion syndrome has been proposed for addition to newborn screening panels. A literature review investigated the incidence and prevalence, clinical features, and prognosis of 22q11 deletion syndrome and other issues related to newborn screening. Severe complications that could potentially be helped by screening include cardiac defects in 80% (with 20% having no outward signs to aid detection), hypocalcemia that can lead to seizures in 20% (though hypocalcemia is routinely investigated in sick newborns), and severe immune deficiency in <1% (which would be identified by some states' severe combined immunodeficiency screens). Other benefits that do not fit traditional goals of newborn screening include treatment for complications such as failure to thrive and developmental delay or preventing a "diagnostic odyssey." Although universal screening may prove the incidence to be >1:5000, undetected life-threatening effects occur in a minority of 22q11 deletion syndrome patients. Concerns include an untested screening technique, difficulty obtaining results in time for cardiac intervention, the chance of "vulnerable child syndrome" in mild cases, and possibly detecting congenital heart disease more efficiently by other means. Because addition of tests for highly variable conditions such as 22q11 deletion syndrome is likely to set a precedent for other syndromes, reevaluation of newborn screening criteria should be considered.

Clinical genetics provider real-time workflow study.

PURPOSE: Our work is the first documentation, in real time, of workflow in a general genetics department including data on patient care, research, and other activities for both clinical geneticists and genetic counselors. METHODS: All physician geneticists and genetic counselors in the medical genetics department used an electronic tool to record their activities in 15 minute increments during clinic hours, evenings, and weekends over a 10-week period. RESULTS: The average work week was 54.1 hours for physicians and 43.5 hours for genetic counselors. During clinic hours physicians spent about one-fourth of their time on direct patient care, one-fourth on other patient-related activities, one-fourth on research unrelated to individual patient care, and the remaining fourth on all other activities. However, after hours and on weekends they spent most of their time on research. Genetic counselors spent half of their time on patient-related activities, one-fourth on direct patient care, and the remainder on all other activities. The total professional time averaged 7 hours per new patient and 3.5 hours per follow-up with nearly 60% of this time devoted to patient-related activities. CONCLUSIONS: The labor intensive nature of clinical genetics, the large amount of time devoted to patient-related activities, and continuing limitations on billing by genetic counselors all contribute to the financial challenges faced by genetics departments.

Prenatal diagnosis of episodic tachypnea in an infant with OFD VI.

Episodic tachypnea is a typical neonatal presentation of Joubert syndrome, but may also occur in infants with other anomalies of the cerebellar vermis. Even though fetuses at risk for Joubert syndrome are usually closely followed by ultrasound, this respiratory pattern has only once been described prenatally. We describe a patient who presented prenatally with posterior meningocele, Dandy-Walker cyst, and four limb polydactyly on ultrasound. Amniocentesis showed a normal male karyotype and normal 7DHC. At 31 weeks, episodic fetal tachypnea was noted on ultrasound. The working diagnosis was Joubert syndrome or oro-facio-digital syndrome type VI (OFD VI). At birth, in addition to the findings noted prenatally, he had multiple nodules of his tongue, a Y-shaped metacarpal and micropenis. His respiratory pattern was notable for alternating tachypnea and apnea with respiratory rates up to 200 followed by apnea and bradycardia. Magnetic resonance image showed Dandy-Walker with massive 4th ventricle, complete absence of the cerebellar vermis, hypoplastic brainstem, and small meningocele. Development is profoundly delayed and he remains ventilator dependent. Both the previously described Joubert patient with prenatally recognized tachypnea, and our patient are atypical for Joubert syndrome since they have polydactyly (which occurs in only 8% of Joubert patients) and hamartomas of the tongue (which occur in 2%). Despite the tongue hamartomas, these patients are not entirely typical for OFD VI, since their polydactyly is postaxial. The observation of prenatal tachypnea in these two patients, but not in typical Joubert patients, suggests they have either a variant of OFD VI or a new Joubert or OFD-like syndrome.

Newborn screening for cystic fibrosis: parents' preferences regarding counseling at the time of infants' sweat test.

Newborn screening (NBS) protocols for cystic fibrosis (CF) are the first regional population-based programs to incorporate DNA analysis into their procedures. Research about these programs can inform policy and practice regarding how best to counsel families with abnormal NBS results. The grounded theory method guided interviews with 33 families whose infants had abnormal CF NBS results. A dimensional analysis of these interviews provided a theoretical framework describing parents' preferences regarding counseling during their infant's sweat test appointment. This framework describes the contexts and characteristics of the two main dimensions of parents' preferences: factual information and emotional support. Factual information included learning about the probability of a CF diagnosis, CF disease facts, sweat test procedure, and CF genetics. Social support consisted of offering parents a choice about the timing and amount of CF information, showing empathy for their distress, instilling hope, personalizing counseling, and providing hospitality. This framework also explains the consequences of counseling that matched versus mismatched parental preferences in these domains. Counseling that matched parents preferences reduced parents' distress while mismatched counseling tended to increase parents' worry about their infant.