Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.

Molecular cytogenetic characterization of the first reported case of inv dup del 20p compatible with a U-type exchange model.

Inverted duplications with terminal deletions have been reported for an increasing number of chromosome ends. The best characterized and most frequent rearrangement reported involves the short arm of chromosome 8. It derives from non-allelic homologous recombination (NAHR) between two inverted LCRs (low copy repeats) of the olfactory receptor (OR) gene cluster during maternal meiosis. We report here on the cytogenetic characterization of the first inversion duplication deletion involving the short arm of chromosome 20 (inv dup del 20p) in an 18-month-old boy presenting with clinical signs consistent with 20p trisomy syndrome. This abnormality was suspected on karyotyping, but high-resolution molecular cytogenetic investigations were required to define the breakpoints of the rearrangement and to obtain insight into the mechanism underlying its formation. The duplicated region was estimated to be 18.16 Mb in size, extending from 20p13 to 20p11.22, and the size of the terminal deletion was estimated at 2.02 Mb in the 20p13 region. No single copy region was detected between the deleted and duplicated segments. As neither LCR nor inversion was identified in the 20p13 region, the inv dup del (20p) chromosome abnormality probably did not arise by NAHR. The most likely mechanism involves a break in the 20p13 region, leading to chromosome instability and reparation by U-type exchange or end-to-end fusion.

Two cases of mosaicism for complex chromosome rearrangements (CCRM) associated with secondary infertility.

Structural chromosomal abnormalities can be associated with infertility through meiosis impairment or the formation of unbalanced gametes. Among these structural abnormalities, complex chromosomal rearrangements (CCR) relate to situations with more than two breakpoints and/or more than two chromosomes involved. Mosaic balanced chromosomal rearrangements are very rare events usually ascertained through infertility, recurrent miscarriages or liveborn abnormal children. Mosaicism for complex chromosome rearrangements (CCRM) has never been described to date. Here we report on two patients with secondary infertility whose karyotype revealed mosaic partially cryptic CCRs, revealed by fluorescence in situ hybridization (FISH). To our knowledge, this is the first report of mosaicism for complex chromosomal rearrangements (CCRM). We discuss the importance of molecular cytogenetic characterization of structural rearrangements to assist in genetic counseling related to the possible use of assisted reproductive technology.

Pure familial 6q21q22.1 duplication in two generations.

Familial transmissions of unbalanced chromosomal abnormalities are rare. We report here the first case of a maternally inherited pure partial duplication of the long arm of chromosome 6 [46,XX,dup(6)(q21q22.1)mat]. The proband was referred for karyotyping as she presented intrauterine growth retardation (IUGR), moderate mental retardation and facial dysmorphism. Molecular cytogenetics analysis with various BACs showed a duplication of 5-10 Mb between 6q21 and 6q22.1. The proband's mother was found to have the same chromosome abnormality and a similar phenotype, but less severe dysmorphism. This variability in clinical findings between generations may have several causes, including attenuation with aging, imprinting or mosaicism. Only three other cases of pure partial 6q duplication similar to that of our case have been reported. The available information for all four cases was used to refine the karyotype-phenotype correlations for duplications of the 6q21q22 segment.

Sperm FISH analysis in two healthy infertile brothers with t(15;18) unbalanced translocation: Implications for genetic counselling and reproductive management.

Numerous studies have shown that balanced reciprocal or Robertsonian translocations and inversions are associated with reduced or absent sperm production. In contrast, a similar association has been rarely reported for unbalanced translocations. An unbalanced translocation, 45,XY,-15,der(18)t(15;18)(q11.2;q23), was found in two healthy infertile brothers who were referred to our hospital together with their partners for infertility. At least two routine semen analyses and karyotyping were done for each of the brothers. Sperm meiotic segregation was studied for both with a three-color FISH assay using locus-specific probes. Semen analyses showed a severe oligo-astheno-teratozoospermia with remarkably similar profiles in the two brothers. The unbalanced translocation had a deletion of 15pter-15q11.2 as well as a deletion of 18q23-18qter. The meiotic segregation was similar in the two brothers with a prevalence of alternate segregation mode. However, no phenotypic effect in the offspring can be expected only if the normal chromosomes 15 and 18 are transmitted to progeny. According to the sperm FISH results, the theoretical probability of this happening is about 25%. Based on the overall results, genetic and reproductive counselling was offered to both couples. Finally, both couples chose the alternative of donor insemination rather than preimplantation genetic diagnosis. The present study helps delineating a phenotypically silent CNV at the distal part of chromosome 18 long arm and illustrates the advantages of an integrated multidisciplinary genetic, reproductive and psychological approach to give the best possible assistance to couples who are faced with a complex and distressing genetic cause of infertility.

First reported case of intrachromosomal cryptic inv dup del Xp in a boy with developmental retardation.

We report here on a 6-year-old boy referred to the laboratory for karyotyping and SHOX microdeletion testing. The most significant clinical findings in this boy were small stature, Madelung deformity, facial dysmorphism, mild mental retardation and behavioral problems. R-, G- and RTBG-banding chromosome analysis showed a normal male karyotype. Fine molecular characterization, by FISH, of terminal Xp microdeletion revealed an associated partial duplication. Further refinement of the molecular analysis indicated an inverted duplication of the Xp22.31-Xp22.32 (13.7 Mb) region including the STS, VCX-A and KAL1 genes, associated with a terminal Xp deletion Xp22.33-Xpter (3.6 Mb) encompassing the SHOX and ARSE genes. Such rearrangements have been characterized for other chromosomal pairs, but this is the first reported male patient involving the short arm of the X chromosome. Molecular analysis of the maternal and patient's microsatellite markers showed interchromatid mispairing leading to non-allelic homologous recombination to be the most likely mechanism underlying this rearrangement. This case highlights the importance of clinically driven FISH investigations in order to uncover cryptic micro-rearrangements.