Portrait of autosomal recessive diseases in the French-Canadian founder population of Saguenay-Lac-Saint-Jean.

The population of the Saguenay-Lac-Saint-Jean (SLSJ) region, located in the province of Quebec, Canada, is recognized as a founder population, where some rare autosomal recessive diseases show a high prevalence. Through the clinical and molecular study of 82 affected individuals from 60 families, this study outlines 12 diseases identified as recurrent in SLSJ. Their carrier frequency was estimated with the contribution of 1059 healthy individuals, increasing the number of autosomal recessive diseases with known carrier frequency in this region from 14 to 25. We review the main clinical and molecular features previously reported for these disorders. Five of the studied diseases have a potential lethal effect and three are associated with intellectual deficiency. Therefore, we believe that the provincial program for carrier screening should be extended to include these eight disorders. The high-carrier frequency, together with the absence of consanguinity in most of these unrelated families, suggest a founder effect and genetic drift for the 12 recurrent variants. We recommend further studies to validate this hypothesis, as well as to extend the present study to other regions in the province of Quebec, since some of these disorders could also be present in other French-Canadian families.

Benefits of Newborn Screening for Vitamin D-Dependant Rickets Type 1A in a Founder Population.

Background: Vitamin D-dependant rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27B1 gene. This gene is essential for vitamin D activation. Although VDDR1A is a rare condition worldwide, its prevalence is high in the Saguenay-Lac-Saint-Jean (SLSJ) region due to a founder effect. Daily intake of calcitriol before the onset of clinical manifestations can prevent them in affected children. Methods: A genetic screening test was developed and validated for the CYP27B1 gene c.262del pathogenic variant. Newborn screening was implemented in the SLSJ region for this variant, and the feasibility and acceptability were assessed. Sixteen medical records of children affected with VDDR1A were reviewed to document the consequences of the disease at diagnosis. Results: A total of 2000 newborns were tested for VDDR1A. Most families (96.5%) accepted the genetic test. We found a carrier rate of 1/29 for the c.262delG variant in our cohort, which is suggestive of a founder effect. We identified one child affected with VDDR1A and treatment was initiated before the onset of clinical manifestations. On average, children with VDDR1A were diagnosed at 13.8 ± 5 months of age, they had a significant failure to thrive at diagnosis, among other harmful health consequences. Conclusion: Our study showed that in our population, the newborn genetic screening program is safe and feasible, it has high acceptability, and it is efficient to identify affected children. VDDR1A health consequences can be prevented by early initiation of treatment. Therefore, screening programs should be available for populations where it is deemed as beneficial from a public health perspective.

French-Canadian families from Saguenay-Lac-Saint-Jean: a new founder population for APECED.

PURPOSE: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is more prevalent in some founder populations, but relatively unexplored in Canada. This study aimed at investigating the French-Canadian patients through phenotypic and genotypic characterization. METHOD: Phenotype and demographic characterization were done for 12 affected individuals belonging to eight unrelated families. Samples from 11 cases were analyzed in a molecular clinical laboratory, and muscle biopsies were reviewed for two individuals with a limb-girdle muscle dystrophy. RESULTS: The clinical phenotype was similar to that observed in European Caucasian populations but differed in the non-endocrine spectrum from the American-reported series of cases. Two cases exhibited a limb-girdle muscle dystrophy, and we found preliminary evidence of a mitochondrial dysfunction, since all three biopsies examined showed COX-deficient fibers in excess of what would be expected for age. Electron microscopy showed mitochondrial accumulation without abnormal cristea or inclusions. The c.1616C > T variant in the AIRE gene was responsible for 100% of APECED cases in the French-Canadian population of Saguenay-Lac-Saint-Jean in Quebec, Canada. CONCLUSIONS: We report the first series of French-Canadian cases affected with APECED. The Saguenay-Lac-Saint-Jean region was uncovered as a new founder population for this condition. Muscle biopsy findings expanded the range of previously described APECED-related myopathology. Long term follow-up of our genetically homogeneous French-Canadian cases may help determine if the c.1616C > T variant increases the risk of muscle involvement. A neonatal screening program is under consideration to prevent undesired life-threatening endocrine manifestations.

First glance at the molecular etiology of hearing loss in French-Canadian families from Saguenay-Lac-Saint-Jean's founder population.

The French-Canadian population of Saguenay-Lac-Saint-Jean is known for its homogenous genetic background. The hereditary causes of hearing loss were previously unexplored in this population. Individuals with hearing loss were referred from the otorhinolaryngology, pediatrics and family physicians' clinics to the medical genetics service at the Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean between June 2015 and March 2021. A regional clinical evaluation strategy was developed. Samples from 63 individuals belonging to 41 families were sent independently to different molecular clinical laboratories and index cases were analyzed through comprehensive multigene panels, with a diagnostic rate of 54%. Sixteen hearing loss causal variants were identified in 12 genes, with eight of these variants not been previously reported in the literature. Recurrent variants were present in four genes, suggesting a possible founder effect, while GJB2 gene variants were scarce. A comprehensive multigene panel approach as part of the proposed clinical evaluation strategy offers a high diagnostic yield for this population.

A Collaborative Model to Implement Flexible, Accessible and Efficient Oncogenetic Services for Hereditary Breast and Ovarian Cancer: The C-MOnGene Study.

Medical genetic services are facing an unprecedented demand for counseling and testing for hereditary breast and ovarian cancer (HBOC) in a context of limited resources. To help resolve this issue, a collaborative oncogenetic model was recently developed and implemented at the CHU de Québec-Université Laval; Quebec; Canada. Here, we present the protocol of the C-MOnGene (Collaborative Model in OncoGenetics) study, funded to examine the context in which the model was implemented and document the lessons that can be learned to optimize the delivery of oncogenetic services. Within three years of implementation, the model allowed researchers to double the annual number of patients seen in genetic counseling. The average number of days between genetic counseling and disclosure of test results significantly decreased. Group counseling sessions improved participants' understanding of breast cancer risk and increased knowledge of breast cancer and genetics and a large majority of them reported to be overwhelmingly satisfied with the process. These quality and performance indicators suggest this oncogenetic model offers a flexible, patient-centered and efficient genetic counseling and testing for HBOC. By identifying the critical facilitating factors and barriers, our study will provide an evidence base for organizations interested in transitioning to an oncogenetic model integrated into oncology care; including teams that are not specialized but are trained in genetics.