Parental mosaicism of JAG1 mutations in families with Alagille syndrome

Abstract

The Alagille syndrome (AGS), a congenital disorder affecting liver, heart, skeleton and eye in association with a typical face, is an autosomal dominant disease with nearly complete penetrance and variable expression. AGS is caused by mutations in the developmentally important JAG1 gene. In our mutation screening, where 61 mutations in JAG1 were detected, we identified five cases where mosaicism is present. Our results point to a significant frequency of mosaicism for JAG1 mutations in AGS of more than 8.2%. Because mosaicism may be associated with a very mild phenotype, the appropriate diagnosis of AGS and consequently the determination of the recurrence risk can be complicated.

Alagille syndrome: pathogenesis, diagnosis and management

“…44 The occasional finding of a cytogenetically visible deletion or rearrangement involving 20p12 was significant in allocating the ALGS locus to this region, 9,45 and the similarity of the phenotype between deletion and mutation cases suggests that haploinsufficiency is the mutational mechanism. Approximately 60% of mutations are de novo, and germline mosaicism may occur at a frequency up to 8%, 46 which must not be overlooked in genetic counselling, where appropriate.…”

Clinical utility gene card for: Alagille Syndrome (ALGS)

“…7 **When screening parents for their child's known mutation, it is important to note that a negative result does not rule out the possibility of germline mosaicism. 12 2.2 Analytical specificity (proportion of negative tests if the genotype is not present) Analytical specificity is nearly 100%. False positives are rare.…”

Alagille syndrome: Chipping away at the tip of the iceberg

“…While mosaicism for alterations in Jagged1 may account for some of the clinical variability seen in this disorder, it is a rarely reported finding. The case presented by LauferCahana et al is the only mosaic 20p12 deletion reported, while other evidence indicates that some individuals may be mosaic for point mutations as well [Giannakudis et al, 2001]. Mosaicism would be an unlikely mechanism for variable expression in large multigeneration families, and the possibility of other genes modifying the severity of the symptoms has been suggested.…”