Original Title: Pertinence d’ajouter deux variants génétiques de la maladie du spectre de Zellweger à l’offre de tests de porteur chez les personnes originaires des régions du Saguenay–Lac-Saint-Jean, de Charlevoix et de la Haute-Côte-Nord

Authors' objectives: Zellweger spectrum disorder (ZSD) is an autosomal recessive peroxisome biogenesis disorder. Several PEX genes coding for peroxins can be responsible for ZSD. Patients with the severe form of this disease will present with various clinical manifestations, including neurological, hepatic, and renal impairments, as well as global developmental delays and heart problems. Death occurs very early: the vast majority of patients with the severe form will die before the age of two. Multiple genetic variants across 14 PEX genes can cause ZSD with varying degrees of severity. Two genetic variants are more prevalent in the Saguenay-Lac-Saint-Jean region and are linked to severe forms of the disease, namely the genetic variant c.2097_2098insT of the PEX1 gene and the genetic variant c.802_815del14 of the PEX6 gene. The variant c.802_815del14 in the PEX6 gene is linked to a founder effect in this region. For a child to have ZSD, both of their biological parents must be carriers of the disease. Currently, in Quebec, ZSD carrier testing is only offered to people with a family history of the disease. Moreover, a carrier screening test for four other recessive inherited diseases is available to people from the Saguenay-Lac-Saint-Jean, Charlevoix, and Haute-CôteNord regions. It allows eligible individuals and couples to obtain their carrier status and information about their reproductive risks for four diseases that have high carrier rates in the population from these regions, so that carrier couples can make informed decisions regarding reproduction. The Ministère de la Santé et des Services Sociaux has mandated the National Institute of Excellence in Health and Social Services to evaluate the relevance of including carrier screening for the PEX1 gene variant c.2097_2098insT and the PEX6 gene variant c.802_815del14, both associated with ZSD, in the current carrier screening test offer for people from the Saguenay-Lac-Saint-Jean, Charlevoix, and Haute-Côte-Nord regions.

Authors' results and conclusions: RESULTS (#1 THE PEX6 GENE VARIANT C.802_815DEL14 AND THE PEX1 GENE VARIANT C.2097_2098INST ARE ASSOCIATED WITH A SEVERE FORM OF ZELLWEGER SPECTRUM DISORDER): The incidence of Zellweger spectrum disorder (ZSD) at birth is significantly higher in the Saguenay-Lac-Saint-Jean region of Quebec, Canada, with 1 in 12,000, compared to the estimated global prevalence of 1 in 50,000. • The genetic variant PEX6 c.802_815del14 is associated with a founder effect in the Saguenay-Lac-Saint-Jean region and is estimated to have a carrier frequency of 1 in 53 in this population. This variant is associated with a severe form of the disease. (#2 THERE IS CURRENTLY NO CURE FOR ZELLWEGER SPECTRUM DISORDER (ZSD): There is currently no cure for ZSD; treatments focus on managing the clinical manifestations by providing supportive care. (#3 SCREENING FOR CARRIER STATUS OF GENETIC VARIANTS IS EFFECTIVE, BUT CARRIES THE RESIDUAL RISK THAT THE INDIVIDUAL MAY BE A CARRIER OF OTHER VARIANTS): Carrier screening for ZSD using TaqMan clinical genotyping shows 100% sensitivity and specificity; The genetic variants c.802_815del14 of the PEX6 gene and c.2097_2098insT of the PEX1 gene represent 76% and 20%, respectively, of the genetic variants responsible for ZSD in the population of the Saguenay-LacSaint-Jean region. (#4 THE OFFER OF CARRIER STATUS SCREENING TESTS IS WELL KNOWN AND ACCEPTED IN THE TARGETED REGIONS, BUT LESS KNOWN OUTSIDE THESE REGIONS): The offer of screening tests for carrier status is well known and accepted in the Saguenay-Lac-Saint-Jean region, and the addition of new diseases to the tests is expected by several groups. • Eligible individuals outside the Saguenay-Lac-Saint-Jean, Charlevoix and HauteCôte-Nord regions are less familiar with the tests on offer. (#5 THE INTEGRATION OF ZSD-ASSOCIATED GENETIC VARIANTS INTO CARRIER SCREENING OFFER DOES NOT POSE SIGNIFICANT ORGANIZATIONAL CHALLENGES): Healthcare professionals could be better informed of the range of tests offered, so that they can recommend these tests to their eligible patients and provide them with further support. • The standardization of the offer of genetic services and their procedures in the context of screening for carrier status is desirable across different regions in Quebec. (#6 THE ECONOMIC IMPACT OF ADDING ZSD GENETIC VARIANTS TO THE CARRIER STATUS SCREENING TEST OFFERING IS MINOR): A temporary increase in participation in carrier status screening test offerings may occur during the first few years following the addition of genetic variants for ZSD. • Certain costs were excluded from the budget impact analysis, including those associated with various reproductive options for carrier couples and those related to the care of newborns with ZSD. (#7 DIFFERENT ETHICAL ISSUES WERE RAISED): A public offer of tests can mitigate inequities between different public and private genetic services in regions for individuals carrying variants of targeted diseases. Conversely, this raises equity issues in relation to populations in other regions that may also experience a high prevalence of certain recessive hereditary diseases. • Some recessive hereditary diseases would have a carrier status frequency similar to that of ZSD at the provincial level, but they are not part of a public test offering, which raises a provincial inequity concerning access to carrier status screening tests.

Authors' recommendations: INESSS recommends adding the genetic variants c.2097_2098insT of the PEX1 gene and c.802_815del14 of the PEX6 gene for Zellweger spectrum disorder to the carrier status screening test offering for recessive hereditary diseases in individuals originating from the Saguenay-Lac-Saint-Jean, Charlevoix, and Haute-Côte-Nord regions. The following considerations were also formulated at the end of the work: • Monitoring of variants included in the carrier status screening test offering for recessive hereditary diseases in individuals originating from the Saguenay-LacSaint-Jean, Charlevoix, and Haute-Côte-Nord regions is essential to remove, if necessary, variants that would not lead to the identification of carrier couples within the target population. • The concept of reproductive autonomy must remain the primary objective of the carrier status screening test offering. Those taking part in the offer and identified carriers must be able to receive timely and relevant information in order to make free and informed decisions without external pressure. The information provided to participants regarding the limitations, consequences, and implications of carrier screening tests could be enhanced in the context of updating the participant kit. • Given the increasing complexity of determining an individual’s origins, ethnicity, and family history, the evolving demographics of the Quebec population should be considered when adapting carrier screening test offer.

Authors' methods: A quick review, that is, is a rigorous and transparent synthesis of the literature, was conducted to document the clinical dimension including the test performance, effectiveness, and safety of carrier screening. A narrative review of the scientific literature was conducted to address the population, organizational, sociocultural, and economic dimensions. Scientific literature and gray literature were identified in multiple databases without restrictions on study designs. Contextual and experiential data were collected from an advisory committee made up of professionals working in the field. Users of the health and social services network were also consulted.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/tests-de-porteur.html

Year Published: 2024

URL for published report: https://www.inesss.qc.ca/fileadmin/doc/INESSS/Rapports/Depistage/INESSS_Statut_porteur_Avis_MSZ.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)