Paternal age effect in autosomal dominant or X-linked de novo variants identified by genome-wide sequencing.

An increased frequency of sporadic autosomal dominant disorders has been observed among children born to older fathers. This paternal age effect is thought to reflect an accumulation of new mutations in the male germ line as DNA replication and cell division continue to occur as men age. Genome-wide sequencing is useful for identifying disease-causing genetic variants in patients with suspected genetic diseases and for determining inheritance or de novo mutation of the variants when done in patient-parent trios. We analyzed paternal ages in 593 families who received trio or quad exome or genome sequencing for suspected genetic disease. The mean age of fathers of children with de novo disease-causing variants (35.09 years) was significantly greater than that of children with inherited disease-causing variants (33.78 years, p = 0.04). The mean age of mothers of children with de novo disease-causing variants (31.86 years) was not significantly greater than that of children with inherited disease-causing variants (30.80 years, p = 0.09). Interestingly, when the de novo disease-causing variants were broken down into subgroups by variant type, both mean paternal age and mean maternal age of children with de novo indel variants (paternal = 36.33 years, maternal = 33.34 years) were significantly higher than in children identified to have de novo single-nucleotide variants (paternal = 34.35 years, p = 0.03; maternal = 31.15 years, p = 0.004). This observation, which may have implications for how indels arise, requires further study.