Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

Abstract

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

“…Genetic neuromuscular and developmental disorders with onset in the first year of life include a variety of monogenic conditions, including AMC, with expanding clinical differential diagnosis, genetic heterogeneity, and associated disease mechanisms (14)(15)(16)(17).…”

SCN1A Mutation—Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis

“…Although over 320 genes have been implicated, exemplifying the genetic heterogeneity of the condition (115), AMC is poorly related to SCN1A, with only two reports documented (93,94). The first report described SCN1A mutations in three infants with AMC from three different families (93).…”

Functional loss of ubiquitin‐specific protease 14 may lead to a novel distal arthrogryposis phenotype

“…Exome sequencing is reported to have a diagnostic yield of 47% to 73% in large MCC cohorts, and a recent study with 315 unrelated families showed that 21% of the variations resided in recently identified genes. [3][4][5][6] This report defines a new recessive antenatal MCC phenotype with underdevelopment of the corpus callosum and dysmorphic features, associated with a homozygous frameshift variant in ubiquitinspecific protease 14 (USP14, MIM 607274) in three fetuses from two related families investigated using exome sequencing. In line with the clinical presentation of the affected cases reported here, mice models deficient for the USP14 ortholog have been shown to display early lethality, muscle wasting, and callosal defects.…”

“…The vast majority of these fetal conditions are of genetic origin, and to date, more than 400 distinct disorders with MCC have been described. Exome sequencing is reported to have a diagnostic yield of 47% to 73% in large MCC cohorts, and a recent study with 315 unrelated families showed that 21% of the variations resided in recently identified genes 3–6 …”