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Genetic burden linked to founder effects in Saguenay-Lac-Saint-Jean illustrates the importance of genetic screening test availability.

ABSTRACT: The Saguenay-Lac-Saint-Jean (SLSJ) region located in the province of Quebec was settled in the 19th century by pioneers issued from successive migration waves starting in France in the 17th century and continuing within Quebec until the beginning of the 20th century. The genetic structure of the SLSJ population is considered to be the product of a triple founder effect and is characterised by a higher prevalence of some rare genetic diseases. Several studies were performed to elucidate the historical, demographic and genetic background of current SLSJ inhabitants to assess the origins of these rare disorders and their distribution in the population. Thanks to the development of new sequencing technologies, the genes and the variants responsible for the most prevalent conditions were identified. Combined with other resources such as the BALSAC population database, identifying the causal genes and the pathogenic variants allowed to assess the impacts of some of these founder mutations on the population health and to design precision medicine public health strategies based on carrier testing. Furthermore, it stimulated the establishment of many public programmes.We report here a review and an update of a subset of inherited disorders and founder mutations in the SLSJ region. Data were collected from published scientific sources. This work expands the knowledge about the current frequencies of these rare disorders, the frequencies of other rare genetic diseases in this population, the relevance of the carrier tests offered to the population, as well as the current available treatments and research about future therapeutic avenues for these inherited disorders.

SUBMITTER: Bchetnia M

PROVIDER: S-EPMC8479736 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. METHODS: Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. RESULTS: We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name "spastic ataxia", neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance. CONCLUSIONS: We here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features - which also extend to supratentorial regions and involve the cerebral cortex - will help to establish the diagnosis in most cases.

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Genetic burden linked to founder effects in Saguenay-Lac-Saint-Jean illustrates the importance of genetic screening test availability.

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