Claude Laberge

Preliminary report on a mass screening program for neonatal hypothyroidism

We have recently developed an immunoassay that can measure thyroxine rapidly and accurately in the eluate of 40 mul of dried blood spotted on filter paper at the fifth day of life. The method is completely automated and by using the samples received by the Central Laboratory of the Quebec Network for Genetic Medicine and their follow-up facilities, we are now screening every newborn in the province of Quebec for neonatal hypothyroidism. To date, from 47,000 measurements, three newborn infants with abnormally low TBG and seven hypothyroid infants have been detected. From these data we conclude that the frequency of congenital hypothyroidism is about one in 7,000 births and that our method is effective in detecting thyroid hormone abnormalities with an acceptable percentage of false positive measurements; no false negative results have occurred to our knowledge.

Community Engagement in Genetic Research: Results of the First Public Consultation for the Quebec CARTaGENE Project

Objective: This paper presents the results of the first public consultation for the creation of a large-scale genetic database, the Quebec CARTaGENE project. A consultation has been undertaken in order to gauge whether the general public is receptive to the project. An integral part of the approach of the researchers is to establish a dialogue with the public. Methods: Two independent expert groups have carried out qualitative and quantitative studies measuring knowledge of and interest in genetics, incentives and obstacles to CARTaGENE participation and comprehension and evaluation of the communication tools. Results: CARTaGENE is seen to hold promise for the greater population. However, reported across qualitative and quantitative studies is the concern for confidentiality and respect for the individual, transparency, the donor’s right to feedback and governance. Participation would be conditional on a response to those concerns and a greater dissemination of information. Conclusion: Community engagement in genetic research requires targeted communications, with an appropriate proportioning of information and communication, and a consideration of the ‘values and personal interests’ of individuals according to different societal segments.

TSH measurements from blood spots on filter paper: A confirmatory screening test for neonatal hypothyroidism

A sensitive radioimmunoassay for the measurement of TSH in the eluate of blood spotted on filter paper has been developed. The method is consistently sensitive to 0.1 to 0.25 muU of TSH and enables the detection of values equivalent to 6 to 15 muU/ml of serum. The measurement of TSH in the filter paper spot in all infants with low filter paper spot T4 has permitted rapid confirmation of 10 cases of neonatal hypothyroidism. However, cases of hypothalamic hypothyroidism with low or normal filter paper spot TSH concentrations would have been missed using only this method. Since these patients represent approximately 10% of our neonatal hypothyroid population, we do not recommend this method as a primary screening procedure, but rather as a confirmatory test which will accelerate the diagnosis and therefore the onset of therapy.

Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinemia

A technique designed to measure quantitatively succinylacetone (4,6-dioxoheptanoic acid) is presented. It essentially involves the inhibition of delta-aminolevulinate dehydratase (EC 4.2.1.24) by succinylacetone. Prior to their use in the assay, the samples are heated at 100 degrees C for 30 min in order to transform all succinylacetoacetate (3,5-dioxooctanedioic acid) to succinylacetone. By this transformation of the first abnormal metabolite specific to hereditary tyrosinemia to the second and last one, which is a powerful inhibitor of delta-aminolevulinate dehydratase, we determine in one sensitive assay the total amount of both. Succinylacetone was measured in sera and urines from 19 patients with hereditary tyrosinemia. All sera and urines contained succinylacetone at concentrations ranging, respectively, from 2 to 100 mumol/l and from 190 to 6000 mumol/g creatinine. The technique was also adapted to dried blood spots on paper and was used as a test complementary to blood tyrosine determination in mass screening for hereditary tyrosinemia. A total of 2412 samples having concentrations of 60 mg/l or more of tyrosine were assayed, and ten showed the presence of succinylacetone. These were all from newborns with hereditary tyrosinemia. The test has proven to virtually eliminate false positives, and, thereby, much clerical work and parental anxiety.

Cohort profile of the CARTaGENE study: Quebec's population-based biobank for public health and personalized genomics.

The CARTaGENE (CaG) study is both a population-based biobank and the largest ongoing prospective health study of men and women in Quebec. In population-based cohorts, participants are not recruited for a particular disease but represent a random selection among the population, minimizing the need to correct for bias in measured phenotypes. CaG targeted the segment of the population that is most at risk of developing chronic disorders, that is 40-69 years of age, from four metropolitan areas in Quebec. Over 20,000 participants consented to visiting 1 of 12 assessment sites where detailed health and socio-demographic information, physiological measures and biological samples (blood, serum and urine) were captured for a total of 650 variables. Significant correlations of diseases and chronic conditions are observed across these regions, implicating complex interactions, some of which we describe for major chronic conditions. The CaG study is one of the few population-based cohorts in the world where blood is stored not only for DNA and protein based science but also for gene expression analyses, opening the door for multiple systems genomics approaches that identify genetic and environmental factors associated with disease-related quantitative traits. Interested researchers are encouraged to submit project proposals on the study website (www.cartagene.qc.ca).

Modification of a screening program for neonatal hypothyroidism

From our experience in the screening of 212,000 newborn infants, we have devised a flow chart for processing T4 and TSH measurements obtained from initial filter paper blood spots. To date, all infants with thyroid dysfunction or TBG deficiency have been detected. Of the population screened, 1.84% require a spot TSH determination, and 1.1% require repeat determinations of T4.

Aspect cytologique et localisation intranucléaire de l'hétérochromatine constitutive des chromosomes C9 chez l'homme

Using a specific technique which stains the secondary constriction of number 9 chromosomes in man, we observed that this segment frequently appears to be composed of multiple small units packed together in metaphase as well as in interphase. During prophase of the first meiotic division in man, this segment looks like a diffuse structure, suggesting division and multiplication of these units. On the other hand, the C9 bodies observed in interphase with this cytological procedure are frequently associated with the nucleolus. This heterochromatin is less compact than previously shown and may represent repetitive DNA with a specific role.

Thyroid function in neonatal hypothyroidism

Various aspects of the thyroid function have been measured in 28 cases of neonatal hypothyroidism detected by means of the Quebec Screening Program for Metabolic Diseases. In all instances the T4 value in the blood of filter paper spot was below 2 SD of the mean of the day, averaging 0.39 +/- 0.04 ng/40 mul (mean +/- SEM) of eluted blood. The T4 value of a second similar sample averaged 0.22 +/- 0.04 ng/mul of eluted blood; this value was significantly lower than the first one. The serum T4 concentration was decreased in all the infants, whereas three of them had a normal serum TSH concentration. At least three groups of patients could be identified: (1) patients with primary thyroid failure, (2) those with secondary or tertiary hypothyrodism, and (3) those with abnormal synthesis of thyroid hormone.

Framing genomics, public health research and policy: points to consider.

Genetic information can be used to target interventions that improve health and prevent disease. Indeed, the results of population genomics research could be useful for public health and national pandemic plans. Yet, firm scientific evidence originating from such research and the indicators of the role of health determinants, gene-gene and gene-environment interaction remain to be assessed and validated before being integrated into pandemic plans or public health programmes. It is not clear what is the role of the State in research on the elucidation of the determinants of gene-gene and gene-environment interactions and how, when, and if such data can be accessed and used for such planning. Over a period of 3 years, we sought to address these questions by gathering data and literature relevant to research in public health genomics, preparing issues papers and, finally, consulting with stakeholders on a provisional ‘points to consider’ document at various times. Examining in turn the issues of privacy, State powers, stakeholder perceptions, and public participation, we propose in this article, for each of these themes, a series of recommendations aiming to provide guidance on the role of the State in the use of genomic information for public health research, prevention and planning.

Psychosocial impact of predictive testing for myotonic dystrophy type 1

In the Saguenay‐Lac‐Saint‐Jean region (Quebec, Canada), a predictive DNA‐testing program for myotonic dystrophy type 1 (DM1) has been available as a clinical service since 1988. From 1 to 12 years (median, 5 years) after receiving predictive testing, a total of 308 participants (44 carriers and 264 non‐carriers) answered a questionnaire to determine the psychosocial impact of this genetic testing. The main reasons for wanting to be tested were to learn if children are at risk for DM1 or for reproductive decision making (75%) and to relieve the uncertainty for themselves (17%). The majority of participants (96.1%) remembered correctly their test result. At the time of the survey, the perception of the general well‐being, the psychological distress (Psychiatric Symptom Index), and the self‐esteem (Rosenberg Self‐Esteem Scale) were similar in carriers, in non‐carriers, and in the reference (Quebec) population. When participants indicated a change in different aspects of their lives following predictive testing, it was perceived as a change for the better by non‐carriers and as a change for the worse by carriers. Nevertheless, for a majority of carriers and of non‐carriers, the test result did not bring changes in their lives. All respondents believed that predictive testing should be available for the at‐risk population and the vast majority of carrier and of non‐carriers would recommend the use of predictive testing to their family members. Predictive testing for individuals at‐risk of DM1 can be offered safely within a well‐organized clinical and genetic counseling program that includes careful pre‐test counseling, pre‐test clinical assessment, post‐test psychological support, and follow‐up for those identified as carriers.