The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance

Abstract

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.

The mutational burden and oligogenic inheritance in Klippel-Feil syndrome

“…Oligogenic inheritance, characterized by the concurrent effect of two or more distinct genes on the resulting phenotype, was subsequently confirmed to apply to other skeletal deformities such as arthrogryposis [45]. Based on the results from previous studies and our findings, the etiology of congenital cervical fusion is unlikely to be fully explained by a monogenetic model for a fraction of patients.…”

Congenital fibrinogen disorder caused by digenic mutations of the FGA and FGB genes

“…For some disorders, the discovery of rare genetic variants and the observation of familial co-segregation in some cases result in the perception that Mendelian inheritance may apply. However, recent advances in genetic tests have revealed several disorders beyond the One Gene-One Disease paradigm, indicatinga more complex inheritance and pleiotropy in heritable disorders [13]. Cerrone et al, reported that oligogenic or polygenic genetic variants contributed to inheritable cardiac disorders [14].…”

Newborn Differential DNA Methylation and Subcortical Brain Volumes as Early Signs of Severe Neurodevelopmental Delay in a South African Birth Cohort Study

“…SPTBN4 (Spectrin Beta, Non-Erythrocytic 4) is a protein coding gene, which is, according to the Human Protein Atlas, primary expressed in brain tissue and particularly in the cerebellum, which is the part of the brain that functions as a co-processor of movement in concert with the cortex and basal ganglia 52 . In line, mutations and loss-of-function variants in SPTBN4 were reported in association with arthrogryposis, which is a neuromuscular condition 53 , and with a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy 54 . To the best of our knowledge, only one study has identified differential DNA methylation in SPTBN4 in association with neurocognitive outcomes (Alzheimer's disease) and this study was conducted in mice 55 .…”