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The intron 22 inversion found in up to 50% of severe hemophilia A patients results from a recombination between three intron 22 homologous copies (int22h). This study evaluated the implication of these copies in the formation of extended duplications comprising exons 1-22 of the factor 8 (F8) gene and their association with hemophilia and mental retardation. Two hemophilic patients with moderate and severe phenotypes and a third nonhemophilic patient with developmental delay were studied. All exhibited a duplication of F8 gene exons 1-22 identified by multiplex ligation-dependent probe amplification along with abnormal patterns on Southern blotting and unexpected long-range PCR amplification. Breakpoint analysis using array comparative genomic hybridization was performed to delimit the extent of these rearrangements. These duplications were bounded on one side by the F8 intragenic int22h-1 repeat and on the other side by extragenic int22h-2 or int22h-3 copies. However, the simultaneous identification of a second duplication containing F8 gene exons 2-14 for the moderate patient and the classical intron 22 inversion for the severe patient are considered in this study as the genetic causal defects of hemophilia. This study shows that the well-known int22h copies are involved in extended duplications comprising F8 gene exons 1-22. These specific duplications are probably not responsible for hemophilia and intellectual disability, but should be carefully considered in genetic counseling, while continuing to investigate the causal mutation of hemophilia.

NF1 microdeletion syndrome is a common dominant genomic disorder responsible for around 5% of type I neurofibromatosis cases. The majority of cases are caused by mutations arising within the NF1 gene. NF1 microdeletion carriers present a more severe phenotype than patients with intragenic mutations, including mental retardation, cardiac anomalies and dysmorphic features. Here, we report on two brothers with mental retardation presenting a microduplication of the NF1 microdeletion syndrome region detected by array-CGH analysis. Main phenotypic features are mental deficiency, early onset of baldness (15 years old), dental enamel hypoplasia and minor facial dysmorphism. The breakpoint regions coincide with the repeats, and the recombination hot spots shown to mediate NF1 microdeletion through NAHR. A screening of the patients' familial relatives showed that this microduplication segregates in the family for at least two generations. This result demonstrates that both deletion and duplication of the NF1 region, at cytogenetic band 17q11.2, give rise to viable gametes, even if only NF1 microdeletions have been reported until now. Our study reports seven cases of NF1 microduplication within one family. Similar phenotypic abnormalities were present in most of the individuals, however, two displayed a normal phenotype, suggesting a potential incomplete penetrance of the phenotype associated with NF1 microduplication.

Key Clinical Message Maternal uniparental disomy of chromosome 14 (upd(14)mat) is responsible for a Prader-Willi-like syndrome with precocious puberty. Although upd(14) is often hypothesized to result from trisomy rescue mechanism, T14 cell lines are usually not found with postnatal cytogenetic investigations. We report the coexistence of both chromosomal abnormalities in a 15-year-old girl. [ABSTRACT FROM AUTHOR]