Original Title: Pertinence d’ajouter un variant génétique de la mucolipidose de type II 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: Mucolipidosis type II (MLII) is an autosomal recessive lysosomal storage disease caused by genetic variants in the GNPTAB gene, encoding two subunits of the Nacetylglucosamine-1-phosphotransferase enzyme. Individuals with MLII exhibit multisystemic impairments, including delayed motor and intellectual development, and typically pass away at a young age. While MLII is a rare disease, its birth prevalence is 1 in 6,184 in the Saguenay-Lac-Saint-Jean region, which is significantly higher than in the general population due to a founder effect. For a child to have MLII, both biological parents must be carriers of the disease. Currently, in Quebec, MLII carrier screening is only offered to individuals with a family history of the disease. The carrier screening test for four recessive hereditary diseases (congenital lactic acidosis, recessive spastic ataxia of Charlevoix-Saguenay, hereditary sensory motor neuropathy with or without agenesis of the corpus callosum and hereditary tyrosinemia type 1) for individuals from the Saguenay-Lac-Saint-Jean, Charlevoix and Haute-Côte-Nord regions enables eligible individuals and couples to obtain their carrier status and information about their reproductive risks in relation to these four diseases, so that carrier couples can make informed decisions regarding reproduction. The ministère de la Santé et des Services Sociaux (MSSS) has mandated the National Institute of Excellence in Health and Social Services (INESSS) to evaluate the relevance of including carrier screening for the c.3503_3504delTC variant in the GNPTAB gene associated with MLII in the current carrier screening program for individuals from the Saguenay-Lac-Saint-Jean, Charlevoix, and Haute-Côte-Nord regions.

Authors' results and conclusions: RESULTS (#1 MLII IS A SEVERE DISEASE WITH A POOR PROGNOSIS FOR AFFECTED INDIVIDUALS): a severe disease with a poor prognosis for affected individuals • MLII is a slowly progressive autosomal recessive lysosomal storage disorder that severely affects several body systems. • A majority of individuals with MLII exhibit symptoms from birth. • The diagnosis is quickly suspected and confirmed by molecular analysis and sequencing of the GNPTAB gene. (#2 MLII IS A RARE DISEASE WITH AN INCREASED PREVALENCE IN SAGUENAY-LAC-SAINT-JEAN AND CHARLEVOIX REGIONS DUE TO A FOUNDER EFFECT): The worldwide birth prevalence of MLII is estimated to be between 1/123,000 and 1/2,000,000, compared with a prevalence of 1/6,184 in Saguenay-Lac-Saint-Jean. • In addition to the Saguenay-Lac-Saint-Jean region, a few cases of MLII have been reported in the Charlevoix region. • The frequency of carrier status of the c.3503_3504delTC variant of the GNPTAB gene would be 1/48 in Saguenay-Lac-Saint-Jean. • According to the few data available, the frequency of carrier status of the c.3503_3504delTC variant of the GNPTAB gene would be significantly lower in the Quebec population not subject to the founder effect, and it is estimated at 1/961. (#3 THE SCIENTIFIC EVIDENCE IS STRONG BETWEEN THE GNPTAB GENE VARIANT AND MLII): • The association between the GNPTAB gene and MLII is definitive, and the genetic variant c.3503_3504delTC of the GNPTAB gene is pathogenic. (#4 THERE IS A RELIABLE AND VALID SCREENING TEST FOR CARRIER STATUS OF THE C.3503_3504DELTC VARIANT OF THE GNPTAB GENE ): The TaqMan genotyping screening test for MLII carrier status using buccal cell self-sampling shows very high sensitivity and specificity. • Despite a negative screening test result, there is a residual risk of carrying another pathogenic variant in the MLII-associated GNPTAB gene. (#5 CARRIER SCREENING TESTING IS WELL KNOWN AND ACCEPTED IN THE TARGETED REGIONS): Carrier screening testing is well known and accepted in the Saguenay-Lac-SaintJean region, and the addition of new diseases 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. (#6 THE INTEGRATION OF THE MLII GENETIC VARIANT INTO CARRIER SCREENING TESTING DOES NOT POSE SIGNIFICANT ORGANIZATIONAL CHALLENGES): • The clinical pathway for participants in carrier testing is well defined and includes genetic counseling support for identified carrier couples. • The integration of MLII carrier test into the existing testing program would have minor impacts on the platform and on genetic counseling needs. • Carrier couples identified through MLII screening would have timely access to healthcare resources, regardless of their location in Quebec. (#7 THE ECONOMIC IMPACT OF ADDING THE MLII GENETIC VARIANT TO THE CARRIER SCREENING TESTING PROGRAM IS MINOR): The estimated net budget impact over three years of adding the MLII variant to the carrier screening testing program is $104,906, while the impact of the 3 variants (2 for ZSD and 1 MLII) is $160,131. (#8 ETHICAL ISSUES RELATED TO MLII CARRIER SCREENING ARE IDENTIFIED): Including the c.3503_3504delTC variant in carrier screening tests can help reduce inequities between different public and private genetic services for individuals eligible for carrier screening. • Given the low prevalence of MLII in other regions of Quebec, adding MLII to the carrier screening test (i.e., only for individuals from the Saguenay-Lac-Saint-Jean, Charlevoix, and Haute-Côte-Nord regions) would be justifiable and acceptable.

Authors' recommendations: INESSS recommends adding the c.3503_3504delTC genetic variant of the GNPTAB gene for mucolipidosis type II to the carrier screening test offer for recessive inherited diseases in people originating from the Saguenay-Lac-Saint-Jean, Charlevoix, and Haute-Côte-Nord regions.The following observations were also made at the end of the work: • Regular monitoring of the variants included in the carrier screening test offer for recessive inherited 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 offer. 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. Healthcare professionals should be better informed about the various carrier screening tests available to better approach and guide at-risk individuals of reproductive age or in early pregnancy towards testing offers. This is important in a context where individuals not residing in targeted regions are eligible for testing. • 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 offers.

Authors' methods: A quick review, that is, a rigorous and transparent synthesis of the literature, was conducted to document the clinical dimension including the test performance, the 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 and gray literature were identified in multiple databases without restrictions on study designs. Contextual and experiential data were collected from members of an advisory committee composed 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_MLII.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)