Germline origins in the human F9 gene: frequent G:C→A:T mosaicism and increased mutations with advanced maternal age

Abstract

The factor IX gene (F9) is an advantageous system for analyzing recent spontaneous germline mutation in humans. Herein, the male:female ratio of mutation ("r") in F9 have been estimated by Bayesian analysis from 59 germline origin families. The overall "r" in F9 was estimated at 3.75. The "r"s varied with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (>1 kb), respectively. The "r" for the two subtypes of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism was detected in 11% of the 45 origin individuals for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated sensitivity of approximately one part in 20). Four of the five defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen. However, an advanced maternal age effect was observed (P=0.03) and was particularly prominent for transversions (average of the 79th percentile when maternal age was normalized for the year of conception). This suggests that an increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.

Maternal low-level somatic mosaicism of Cys155Tyr of F9 in severe hemophilia B

“…It was reported that maternal mosaicism accounts for a significant proportion of the origin of sporadic cases in hemophilia A [8][9][10]. Although systematic studies are limited for mosaicism in hemophilia B, there have been reports on the cases of mosaicism of F9 mutations [11][12][13][14][15]. In our previously reported series, sporadic cases accounted for 60% of Korean patients with hemophilia B [2], and a significant proportion of these cases could have been from maternal mosaicism.…”

“…In sporadic hemophilia A, CpG transition point mutations from the maternal origin account for the majority of cases of somatic mosaicism [10]. On the other hand, non-CpG transition was the predominant type of mutation in sporadic hemophilia B not only originating from the mother, but also frequently traced up to either maternal grandmother or grandfather [11,12]. Thus, suspicion of the mosaicism is particularly relevant in a sporadic proband with hemophilia with transition point mutations.…”

Mosaics and haemophilia

“…In contrast, older females have a slightly higher likelihood of bearing a de novo germline mutation for haemophilia compared with younger females [23,38].…”

“…Current test methods may not pick up a low level of mosaicism in white cells. So far, in one series [19], mosaicism was proven in 13% of those individuals in whom mutations for haemophilia A originated, and in another series [23], in 11% of individuals in whom mutations for haemophilia B originated. Test methods for mosaicism are improving and leading to the identification of more mosaic individuals.…”

Phenotypic and genotypic characterization of four factor VII deficiency patients from central China

“…Tyr128 located in the epidermal growth factor 1 (EGF1) domain is a highly conserved residue. Three mutations at the analogous residue in FIX (p.Tyr115) had been described in hemophilia B [12][13][14]. It is likely that the introduction …”