Interactive e-counselling for genetics pre-test decisions: where are we now?

In-person genetic counselling (GC) is the model typically used to provide patients with information regarding their genetic testing options. Current and emerging demand for genetic testing may overburden the health care system and exceed the available numbers of genetic counsellors. Furthermore, GC is not always available at times and places convenient for patients. There is little evidence that the in-person model alone is always optimal and alternatives to in-person GC have been studied in genetics and other areas of health care. This review summarizes the published evidence between 1994 and March 2014 for interactive e-learning and decisional support e-tools that could be used in pre-test GC. A total of 21 papers from 15 heterogeneous studies of interactive e-learning tools, with or without decision aids, were reviewed. Study populations, designs, and outcomes varied widely but most used an e-tool as an adjunct to conventional GC. Knowledge acquisition and decisional comfort were achieved and the e-tools were generally well-accepted by users. In a time when health care budgets are constrained and availability of GC is limited, research is needed to determine the specific circumstances in which e-tools might replace or supplement some of the functions of genetic counsellors.

Incidental findings from clinical genome-wide sequencing: a review.

There are several unresolved challenges associated with the clinical application of genome-wide sequencing technologies. One of the most discussed issues is incidental findings (IF), which are defined as discoveries made as a result of genetic testing that are unrelated to the indication for the test. The discussion surrounding IF began in the context of research, which we have used to frame consideration of IF in the clinical context. There is growing consensus that analytically valid and medically actionable IF should be offered to patients, but whether and to what extent clinicians should disclose other kinds of IF is debated. While others have systematically reviewed the literature concerning genetic IF, previous reviews focus on ethical and research-related issues and do not consider the implications for the genetic counseling profession specifically. This review discusses the practical considerations, ethical concerns and genetic counseling issues related to IF, with a particular focus on clinical genome-wide sequencing. To date, the bulk of the literature with respect to IF in the clinical context consists of commentaries, reviews and case reports. There is a need for more empirical studies to provide a foundation for institutional protocols and evidence-based clinical practice standards.

Associations of osseous abnormalities in Neurofibromatosis 1.

The characteristic sites of Neurofibromatosis 1-associated osseous manifestations are the long bones (usually the tibia and fibula), vertebrae and sphenoid wing. Although these focal bony lesions may cause profound clinical consequences, a minority of people with NF1 are affected. However, most people with NF1 are shorter than expected for their age, gender and family. The pathogenesis of NF1 focal osteopathy and its relationship, if any, to short stature are unknown. We examined associations between the occurrence of various osseous lesions in 3377 NF1 probands from the Children's Tumor Foundation NF International Database. Using logistic regression analysis among 260 NF1 probands who had undergone radiological examination of both the spine and skull, we found associations between the occurrence of sphenoid wing and long bone osteopathy (conditional odds ratio [OR] = 6.1; 95% confidence interval [CI] = 1.7-22.3; P = 0.006) and between sphenoid wing and vertebral osteopathy (OR = 16.9; 95% CI = 5.3-53.3; P < 0.001) after adjusting for age and gender. Similar findings were observed from all 3377 NF1 probands using a multivariate probit regression model. In a separate analysis, we found lower age- and gender-standardized height in patients who had characteristic vertebral or sphenoid wing lesions than in people who did not (P < 0.05). We found no relationship between height and tibial osteopathy. We conclude that some people with NF1 are more likely to develop osseous manifestations than others and speculate that there may be a common pathogenetic mechanism responsible for the development of osseous abnormalities and that of the vertebrae and long bones.

Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1).

Children with neurofibromatosis 1 (NF1) often develop low-grade gliomas, but brain tumors are infrequently encountered in adults with NF1. The authors present evidence from two clinical series, one including patients known to have NF1 and another focusing on adults with new onset brain tumors, that suggests an association between NF1 and symptomatic gliomas in older individuals. They also summarize the clinical data on 17 adolescents or adults with NF1 and symptomatic gliomas. The findings suggest that individuals with NF1 are at increased risk of developing gliomas throughout their lives.

Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1.

Five percent of individuals with neurofibromatosis type 1 (NF1) present with congenital long bone pseudarthrosis (PA). In large series, 50-80% of patients with congenital long bone PA also have NF1. Very little information exists on the natural history and pathogenesis of PA in NF1. This report is a descriptive analysis of a large series of patients with NF1 and tibial bowing or PA. Study A is a case-control study using the National Neurofibromatosis Foundation International Database (NNFFID). Eighty-five patients with PA were compared to a control group from the same database. There was a statistically significant male predominance of NF1 cases with PA (54 males to 31 females), compared to controls (85 males to 87 females) (chi2 = 4.0, P = 0.046, using a two-tailed test with Yates' correction). There was no significant difference in the clinical presentation of NF1 manifestations in NF1 patients with PA than in NF1 patients without PA. Of the affected individuals with PA, there were 24 de novo cases and 21 familial cases (9 through maternal and 12 through paternal inheritance). Questions that could not be answered by Study A were addressed by a partially overlapping case-series report, Study B, in which data on 75 cases ascertained through questionnaires completed by NF center directors were collected. From Study B we determined that half of the patients who had a fracture sustained it before age 2, and approximately 16% of the pseudarthrosis patients had an amputation. Our data indicate a male predominance and no parent-of-origin effect. Male gender may be a susceptibility factor for pseudarthrosis in NF1.

Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients.

Type 1 Neurofibromatosis, NF1, is a common genetic disorder with variable clinical manifestations. Although NF1 often is only of cosmetic concern, serious and even lethal complications may occur. It is not possible to predict which symptoms will develop in any affected individual. The NNFF International Database is a multicentre collaborative system for collecting information about this condition. At the time of this analysis, complete clinical information was available on 1,479 probands and 249 of their affected relatives with NF1. On average, the age at diagnosis of NF1 was 8 years younger in the probands than in the affected relatives (P<.01). Many of the manifestations of NF1 were more frequent in the probands than in their affected relatives. The age-specific prevalence of most manifestations of NF1 increases with age. Despite biases inherent in a convenience sample from specialist clinics, the frequencies of many of the serious manifestations of NF1 are similar to those of two smaller population-based studies. The frequencies in this study are likely representative of patients seen at specialized clinics.

Linkage analysis of X-linked cleft palate and ankyloglossia in Manitoba Mennonite and British Columbia Native kindreds.

A locus (CPX) responsible for X-linked cleft palate and ankyloglossia was previously mapped to the proximal long arm of the X chromosome through DNA marker linkage studies in two large kindred: an Icelandic family and a British Columbia (B.C.) Native family. In this study, additional linkage analyses have been performed in the B.C. family and in a newly identified Manitoba Mennonite family with X-linked cleft palate and ankyloglossia. The Manitoba CPX locus maps to the same region as Icelandic and B.C. CPX. Two-point disease-to-marker linkage analyses in the Manitoba family indicate a maximum lod score (Zmax) between CPX and DXS349 (Zmax = 3.33 at theta = 0.0). In multipoint linkage analysis, combined data from the B.C. and Manitoba families suggest that the most likely location for CPX is at DXS447 in Xq21.1 (multipoint Z = 13.5). The support interval for CPX at DXS447 extends approximately from PGK1 to DXYS1 and includes a newly isolated polymorphic locus DXS1109.

The gene responsible for X-linked cleft palate (CPX) in a British Columbia native kindred is localized between PGK1 and DXYS1.

Human craniofacial malformations are a class of common congenital anomalies in which the etiology is heterogeneous and often poorly understood. To better delineate the molecular basis of craniofacial development, we have undertaken a series of experiments directed toward the isolation of a gene involved in human secondary palate formation. DNA marker linkage studies have been performed in a large British Columbia (B.C.) Native family in which cleft palate segregates as an X-linked trait. We have examined 62 family members, including 15 affected males and 8 obligate carrier females. A previous clinical description of the clefting defect in this kindred included submucous cleft palate and bifid or absent uvula. Our recent reevaluation of the family has indicated that ankyloglossia (tongue-tie) is also a feature of X-linked cleft palate in some of the affected males and carrier females. Ankyloglossia has previously been associated with X-linked cleft palate in an Icelandic kindred in which a gene responsible for cleft palate (CPX) was assigned to the Xq21.3-q22 region between DXYS12 and DXS17. For the B.C. kindred reported here, we have mapped the gene responsible for cleft palate and/or ankyloglossia to a more proximal position on the X chromosome. No recombination was observed between B.C. CPX and the DNA marker DXS72 (peak lod score [Zmax] = 7.44 at recombination fraction [theta] = .0) localized to Xq21.1. Recombination was observed between CPX and PGK1 (Zmax = 7.35 at theta = .03) and between CPX and DXYS1 (Zmax = 5.59 at theta = .04). These recombination events localize B.C. CPX between PGK1 and DXYS1 in the Xq13-q21.31 region.