CLINICAL REPORT Unexpected Finding of a Paternal Premutation of the Fragile X FMR1 Gene in a Female Fetus of a Premutation Carrier Mother M. Grazia Pomponi, 1 Roberta Pietrobono, 1 Caterina Neri, 2 Pietro Chiurazzi, 1 and Giovanni Neri 1 * 1 Institute of Medical Genetics, Catholic University, Rome, Italy 2 Institute of Obstetrics and Gynecology, Catholic University, Rome, Italy Received 2 September 2009; Accepted 18 October 2009 We report on the fortuitous finding of a paternal premutation of the FMR1 gene during prenatal diagnosis in a female fetus whose mother was known to be a premutation carrier. Analysis of the DNA, extracted from cultured cells obtained by chorionic villus sampling, demonstrated the presence in the fetus of two FMR1 alleles of 23 and 71 CGG repeats, respectively. Chromosome analysis confirmed a normal female karyotype. The mother was known to be carrier of a normal allele of 23 repeats and a premutation of 79 repeats. Because the 23-CGG repeat allele is uncommon, we wanted to confirm its presence in the father, also given that a reduction in size from 79 to 71 repeats of the putative maternal allele is an unlikely event. Analysis of the father’s DNA did in fact show that he is a carrier of a 69-CGG premutated allele. Therefore, the fetus inherited the normal 23-CGG allele from the mother and the 71-CGG allele from the father. Although a parental couple composed of two premutation carriers is rare, this case illustrates the importance of characterizing both pa- rental genotypes when the results of prenatal diagnosis suggest an unusual segregation of the mutant and/or normal allele. Ó 2010 Wiley-Liss, Inc. Key words: fragile X syndrome; FMR1 gene; male premutation carriers; chorionic villus sampling INTRODUCTION Fragile X syndrome (FXS) (OMIM #300624) is the most common cause of inherited mental retardation, affecting approximately 1 in 4,000 males and 1 in 8,000 females [Terracciano et al., 2005]. FXS is almost invariably due to the expansion of a CGG repeat in the 5 0 -UTR of the FMR1 gene located on the long arm of the X chromosome in region Xq27.3 [Oostra and Chiurazzi, 2001]. FXS was the first human genetic disorder associated to the meiotic instability of a trinucleotide repeat that changes over the genera- tions representing a so-called ‘‘dynamic mutation.’’ Therefore, individuals in the same pedigree usually have a different expansion in the CGG repeat and, due to mitotic instability, a patient with FXS can display a range of alleles with various expansions. Three classes of alleles have been described at the FMR1 locus: (1) wild-type alleles with approximately 10–55 CGG repeats (mode at 30 repeats); (2) ‘‘full mutation’’ alleles with more than 200 CGG repeats, associated with the transcriptional inactivation of the gene and with FXS; (3) ‘‘premutation’’ alleles with approximately 56–200 CGG repeats that still allow gene transcription and do not cause FXS, but are highly unstable and can easily expand to full mutation in the next generation when carried by a female [Fernandez-Carvajal et al., 2009a]. The expansion to full mutation depends on the sex of the carrier. Male carriers, including full mutation carriers, always transmit a premutation to their daugh- ters, possibly because of a germ line selection process [Malter et al., 1997]. When the mother carries a premutation, the probability of expansion is related to the size of the premutation, that is, large premutations (>100 CGGs) usually expand to full mutation alleles, while small premutations (e.g., 56–70 CGGs) can be passed on with only minimal size changes. The mechanism underlying small changes is supposed to be ‘‘replication slippage’’ [Chiurazzi et al., 1994], while the mechanism causing the ‘‘jump’’ from premutation to full mutation alleles is not well understood and may involve errors in DNA repair. Premutations have only recently been associated with human disease, namely premature ovarian failure (POF) in females [Rohr et al., 2008] and a late-onset condition characterized by neuro- degeneration, tremor, and ataxia (FXTAS) in males [Hagerman and *Correspondence to: Giovanni Neri, M.D., Institute of Medical Genetics, Catholic University, Largo F. Vito 1, 00168 Rome, Italy. E-mail: gneri@rm.unicatt.it Published online 15 January 2010 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33213 How to Cite this Article: Pomponi MG, Pietrobono R, Neri C, Chiurazzi P, Neri G. 2010. Unexpected finding of a paternal premutation of the fragile X FMR1 gene in a female fetus of a premutation carrier mother. Am J Med Genet Part A 152A:409–412. Ó 2010 Wiley-Liss, Inc.