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.

Placental Epigenome-Wide Association Study Identified Loci Associated with Childhood Adiposity at 3 Years of Age.

The aim of this study was to identify placental DNA methylation (DNAm) variations associated with adiposity at 3 years of age. We quantified placental DNAm using the Infinium MethylationEPIC BeadChips. We assessed associations between DNAm at single-CpGs and skinfold thickness using robust linear regression models adjusted for gestational age, child's sex, age at follow-up and cellular heterogeneity. We sought replication of DNAm association with child adiposity in an independent cohort. We quantified placental mRNA levels for annotated gene using qRT-PCR and tested for correlation with DNAm. Lower DNAm at cg22593959 and cg22436429 was associated with higher adiposity (ß = -1.18, q = 0.002 and ß = -0.82, q = 0.04). The cg22593959 is located in an intergenic region (chr7q31.3), whereas cg22436429 is within the TFAP2E gene (1p34.3). DNAm at cg22593959 and cg22436429 was correlated with mRNA levels at FAM3C (rs = -0.279, p = 0.005) and TFAP2E (rs = 0.216, p = 0.03). In an independent cohort, the association between placental DNAm at cg22593959 and childhood adiposity was of similar strength and direction (ß = -3.8 ± 4.1, p = 0.36), yet non-significant. Four genomic regions were also associated with skinfold thickness within FMN1, MAGI2, SKAP2 and BMPR1B genes. We identified placental epigenetic variations associated with adiposity at 3 years of age suggesting that childhood fat accretion patterns might be established during fetal life.

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels.

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5'-C-phosphate-G-3' (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother-child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (ß = -2.69, p = 0.05) and fat distribution (ß = -0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (ß = -0.01, p = 0.04) and neonatal leptinemia (ß = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.