Pathogenic variants carrier screening in New Brunswick: Acadians reveal high carrier frequency for multiple genetic disorders

Abstract

Background: Founder populations that have recently undergone important genetic bottlenecks such as French-Canadians and Ashkenazi Jews can harbor some pathogenic variants at a higher carrier rate than the general population, putting them at a higher risk for certain genetic diseases. In these populations, there can be considerable benefit to performing ethnic-based or expanded preconception carrier screening, which can help in the prevention or early diagnosis and management of some genetic diseases. Acadians are descendants of French immigrants who settled in the Atlantic Coast of Canada in the seventeenth century. Yet, the Acadian population has never been investigated for the prevalence/frequency of disease-causing genetic variants.

Methods: An exome sequencing panel for 312 autosomal recessive and 30 X-linked diseases was designed and specimens from 60 healthy participants were sequenced to assess carrier frequency for the targeted diseases.

Results: In this study, we show that a sample population of Acadians in South-East New Brunswick harbor variants for 28 autosomal recessive and 1 X-linked diseases, some of which are significantly more frequent in comparison to reference populations.

Conclusion: Results from this pilot study suggests a need for further investigation of genomic variation in this population and possibly implementation of targeted carrier and neonatal screening programs.

Keywords: Acadians; Carrier screening; Founder population; Inherited disease.

Fig. 1

Distribution of the pathogenic variants in the 60 participants. The two variants were detected in the MTHFR (NM_005957.4) gene: the c.665C > T variant only (in green) or c.665C > T and c.1286A > C (in blue). Three variants were found in SLC17A5 (NM_012434.4): 1 c.533del, 2 c.918T > G and 3 c.819 + 1G > A. Two variants were found in DPYD (NM_000110.3): 4 c.1905 + 1G > A and 5 c.2846A > T. Two variants were present in ACADM (NM_000016.5): 6 c.199T > C, 7 c.250C > T. The CYP27B1 gene (NM_000785.3) also harbored two variants: 8 c.1319_1325dup, 9 c.262del. The USH2A gene (NM_206933.2) also had two variants: 10c.4338_4339del, 11 c.2276G > T. The participant P009 was homozygous for the NPHS2 variant and participants P005 and P025 were homozygous for the MTHFR variant