Identification of large NF1 duplications reciprocal to NAHR-mediated type-1 NF1 deletions.

Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.

Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping.

We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.6 Mb microduplication involving a portion of the minimal deletion critical region in a 15-year-old male with short stature, mild mental retardation, attention deficit hyperactivity disorder, Asperger syndrome, decreased joint mobility, digital abnormalities, and characteristic facial features. Some of these features are shared with a recently reported case with a 15q24 microduplication involving the minimal deletion critical region. We also report two siblings and their mother with duplication adjacent and distal to this region exhibiting mild developmental delay, hypotonia, tapering fingers, characteristic facial features, and prominent ears. The deletion and duplication breakpoints were mapped by array comparative genomic hybridization and the genomic structure in 15q24 was analyzed further. Surprisingly, in addition to the previously recognized three low-copy repeat clusters (BP1, BP2, and BP3), we identified two other paralogous low-copy repeat clusters that likely mediated the formation of alternative sized 15q24 genomic rearrangements via non-allelic homologous recombination.

Unexpected survival in a case of prenatally diagnosed non-mosaic trisomy 22: Clinical report and review of the natural history.

Over 30 cases of complete non-mosaic trisomy 22 have been reported in the literature in the last 20 years [Crowe et al., 1997: Am J Med Genet 71:406-413]. Twenty-two infants were liveborn with an average life expectancy of four days. Of these, nine survived beyond the first two weeks of life. The life span ranged from minutes to 3 years of age. We report a case of an infant diagnosed prenatally with complete non-mosaic trisomy 22. Options such as aggressive medical/surgical intervention or limiting interventions to symptomatic care including home hospice were discussed openly. Given this information, the family elected to provide minimal supportive measures with pediatric hospice. The infant lived for 2 months with her family before her death. Numerous medical and surgical complications are associated with this disorder. Both the family and the medical team must be prepared for in utero fetal demise, stillbirth, or for limited life expectancy. Proper management, therefore, depends upon an understanding of the diagnosis.