Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay is an early onset form of hereditary spastic paraplegia with a peculiar clinical presentation. In addition to cerebellar findings which manifest first with ataxic gait in early life and spasticity, on an evolutionary basis, there is axonal neuropathy, prominent myelinated fibers in the optic fundus, and evidence of cerebellar atrophy that can be detected by cranial MRI. Intelligence is usually normal, however lower IQs have also been documented. This disorder mainly originates from the Charlevoix-Saguenay region of Quebec. Here, we report two Turkish families linked to the disease locus on chromosome 13 q12. There was homozygosity and segregation of disease haplotypes in both families. This form of spastic ataxia may be more common than originally presumed.