Confirmation of paternity suggests a new mutation in the factor VII gene: ‘Pater certus quouque est’ ‐ Response to Girolami <i>et al</i>

Thank you for giving us the opportunity to respond to the comments made by Dr Girolami and colleagues concerning our paper describing a patient with severe factor VII deficiency (Hewitt et al, 2005). In our paper, we proposed that the severe deficiency arose from a previously undetected maternal deletion of a region of chromosome 13 (including the factor VII and factor X genes) together with a new paternal point mutation. Dr Girolami and colleagues suggested that (i) germinal mosaicism in the father and (ii) different paternity could also explain the results in our paper. Concerning the paternity, we did state in our paper that paternity was confirmed using the commercially available AmpFlSTR Identifiler polymerase chain reaction Amplification Kit (Applied Biosystems). In addition, this kit was used to verify relationships between all familial samples and rule out any possibility of sample mis-identification. However, Dr Girolami and colleagues are correct in pointing out that we did not give details of the results in our paper. In fact, the short tandem repeat (STR) analysis confirmed paternity by using 16 different STR alleles including the amelogenin allele that distinguishes between the X- and Y-chromosomes. The proband's family is Caucasian, so using the statistics supplied with the kit (for the US Caucasian population), the STR analysis had a power of discrimination of 1 in 2·00 × 1017, giving an average probability of paternity exclusion of 0·9999992. For this reason, we suggested that the g.3907G > A change represented a new paternal mutation that changes the codon for Glu29 to Lys (E29K). We agree with Dr Girolami and colleagues that the mechanism that gave rise to this mutation could be germinal mosaicism in the father. In this case, the mutation occurs postzygotically in the parent, rather than during meiosis. Germinal mosaicism has been described in many conditions including Duchenne muscular dystrophy (Bakker et al, 1987; Bunyan et al, 1994; van Essen et al, 2003), osteogenesis imperfecta (Raghunath et al, 1995) and pseudoachondroplasia (Hall et al, 1987; Ferguson et al, 1997). Typically, it is observed in dominant (and X-linked recessive) disorders, and is much less common in autosomal recessive diseases (Cserhalmi-Friedman et al, 2002). This may partially reflect ascertainment bias because of the rarity of a mating occurring between a carrier of an autosomal recessive disorder and a germline mosaic for the same disorder. We agree that germinal mosaicism indeed could be investigated by sperm analysis. In summary, because paternity was confirmed, we believe that we have identified a new mutation in the factor VII gene that may have arisen either (i) postzygotically in the father, (ii) during meiosis in the father, or (iii) postzygotically in the proband, but at such a moment and cell type that her factor VII-producing cells (liver hepatocytes) and leucocytes harbour the mutation.

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