Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

Population history and its impact on medical genetics in Quebec.

Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.

KIF1A, an Axonal Transporter of Synaptic Vesicles, Is Mutated in Hereditary Sensory and Autonomic Neuropathy Type 2

Understanding the genetic mutations that cause hereditary sensory and autonomic neuropathies (HSANs) is crucial to identify new therapeutic targets for patients with these neurodegenerative diseases. Rotthier et al. review the currently known genetics of the HSANs, discussing the new findings that provide insights into the mechanisms of disease and highlighting how these discoveries could improve treatment for patients with these diseases. Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders of the PNS. Progressive degeneration, predominantly of sensory and autonomic neurons, is the main pathological feature in patients with HSAN, and causes prominent sensory loss and ulcerative mutilations in combination with variable autonomic and motor disturbances. Advances in molecular genetics have enabled identification of disease-causing mutations in 12 genes, and studies on the functional effects of these mutations are underway. Although some of the affected proteins—such as nerve growth factor and its receptor—have obvious nerve-specific roles, others are ubiquitously expressed proteins that are involved in sphingolipid metabolism, vesicular transport, transcription regulation and structural integrity. An important challenge in the future will be to understand the common molecular pathways that result in HSANs. Unraveling the mechanisms that underlie sensory and autonomic neurodegeneration could assist in identifying targets for future therapeutic strategies in patients with HSAN. This Review highlights key advances in the understanding of HSANs, including insights into the molecular mechanisms of disease, derived from genetic studies of patients with these disorders.

Mechanisms of disease in hereditary sensory and autonomic neuropathies

Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs∗31], c.4804C>T [p.Arg1602∗], and c.7477C>T [p.Arg2493∗]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.

Mutations in C5ORF42 Cause Joubert Syndrome in the French Canadian Population

HereditarysensoryandautonomicneuropathytypeII�(HSANII)�isanearly-onsetautosomalrecessivedisorder� characterizedbylossofperceptiontopain,�touch,�andheatduetoalossofperipheralsensorynerves.�Muta- tionsinhereditarysensoryneuropathytypeII�(HSN2),�asingle-exonORForiginallyidentifiedinaffected� familiesinQuebecandNewfoundland,�Canada,�werefoundtocauseHSANII.�WereportherethatHSN2 is� anervoussystem-specificexonofthewith-no-lysine(K)-1�(WNK1)�gene.�WNK1 mutationshavepreviously� beenreportedtocausepseudohypoaldosteronismtypeIIbuthavenotbeenstudiedinthenervoussystem.� GiventhehighdegreeofconservationofWNK1�betweenmiceandhumans,�wecharacterizedthestructureand� expressionpatternsofthisisoforminmice.�ImmunodetectionsindicatedthatthisWnk1/Hsn2 isoformwas� expressedinsensorycomponentsoftheperipheralnervoussystemandCNSassociatedwithrelayingsensory� andnociceptivesignals,�includingsatellitecells,�Schwanncells,�andsensoryneurons.�Wealsodemonstrate� thatthenovelproteinproductofWnk1/Hsn2�wasmoreabundantinsensoryneuronsthanmotorneurons.� ThecharacteristicsofWNK1/HSN2�pointtoapossibleroleforthisgeneintheperipheralsensoryperception� deficitscharacterizingHSANII.

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Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Background: Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2. Objectives: To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype. Methods: Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations. Results: A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudiere region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype. Conclusions: Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.

A. M. Sarrazin

Papers

Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.