Genetics of neurofibromatosis 1 in Japan: mutation rate and paternal age effect

Abstract

We have performed formal genetic studies on 26 patients (14 males, 12 females) with neurofibromatosis 1 (von Recklinghausen's disease, NF1) in Japan. Family studies of 74 members of 18 kindreds revealed that 50% of the cases were caused by a new mutation; the mutation rate was assumed to be 7.3-10.5 x 10(-5). A tendency of paternal age effect, which was not accounted for by the maternal age effect, was observed, but live-birth order had no significant effect. Genetic linkage of neurofibromatosis 1 to the NF1 gene or the genetic marker in the pericentric region of chromosome 17 was established in 3 informative families.

Epidemiology of neurofibromatosis type 1

“…Available data regarding paternal age in NF1 are inconsistent [Borberg, 1951;Sergeyev, 1975;Riccardi et al, 1984;Huson et al, 1989a;Samuelsson and Akesson, 1989;Clementi et al, 1990;Takano et al, 1992;North, 1993;Bunin et al, 1997]. The largest reported study of this issue is that of Riccardi et al [1984], which included 187 NF1 patients born to apparently unaffected parents.…”

“…A positive family history is present in about half of all NF1 cases [Crowe et al, 1956;Brasfield and Das Gupta, 1972;Carey et al, 1979;Huson et al, 1989a;Samuelsson and Akesson, 1989;Clementi et al, 1990;Littler and Morton, 1990;Takano et al, 1992;North, 1993;Poyhonen et al, 1997]. If one assumes that penetrance is complete, this means that about half of all NF1 patients represent new mutations.…”

“…If one assumes that penetrance is complete, this means that about half of all NF1 patients represent new mutations. Estimates of the rate of new NF1 mutations vary from 1/7,800 to 1/23,000 gametes [Crowe et al, 1956;Sergeyev, 1975;Samuelsson and Akesson, 1989;Huson et al, 1989a;Clementi et al, 1990;Littler and Morton, 1990;Takano et al, 1992]. This…”

A novel NF1 frame-shift mutation (c.702_703delGT) in a Chinese family with neurofibromatosis type 1

“…The NF1 gene was first associated with NF1 in 1990 and is located on chromosome 17q11.2, spanning 350 kbp of genomic DNA and containing 60 exons that encode the 2818 amino acid protein neurofibromin Viskochil et al, 1990;Wallace et al, 1990). The NF1 mutation rate is among the highest observed in human genes, with estimates ranging from 1/7800 to 1/23,000 gametes (Huson et al, 1989;Clementi et al, 1990;Littler and Morton, 1990;Riccardi, 1992;Takano et al, 1992;Li et al, 1995). To date, more than 800 independent mutations in the NF1 gene among different ethnic groups have been described to be associated with neurofibromatosis type 1 (Heim et al, 1995;Origone et al, 2002;Cai et al, 2005;Bausch et al, 2007;Upadhyaya et al, 1997Upadhyaya et al, , 2008Bottillo et al, 2009;Messiaen et al, 2011).…”

“…To date, more than 800 independent mutations in the NF1 gene among different ethnic groups have been described to be associated with neurofibromatosis type 1 (Heim et al, 1995;Origone et al, 2002;Cai et al, 2005;Bausch et al, 2007;Upadhyaya et al, 1997Upadhyaya et al, , 2008Bottillo et al, 2009;Messiaen et al, 2011). About half of NF1 individuals have a positive family history (Clementi et al, 1990;Takano et al, 1992;North, 1993). In this study, alterations in the NF1 gene were analyzed in a three-generation family containing 8 members, and a novel frame-shift mutation was found.…”