NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

Abstract

Purpose: Neurofibromatosis, type 1 (NF1) is an autosomal dominant disorder caused by mutations of the neurofibromin 1 (NF1) gene at 17q11.2. Approximately 5% of individuals with NF1 have a 1.4-Mb heterozygous 17q11.2 deletion encompassing NF1, formed through nonallelic homologous recombination (NAHR) between the low-copy repeats that flank this region. NF1 microdeletion syndrome is more severe than NF1 caused by gene mutations, with individuals exhibiting facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. Although NAHR can also cause reciprocal microduplications, reciprocal NF1 duplications have been previously reported in just one multigenerational family and a second unrelated proband. methods:We analyzed the clinical features in seven individuals with NF1 microduplications, identified among 48,817 probands tested in our laboratory by array-based comparative genomic hybridization. Results:The only clinical features present in more than one individual were variable DD/ID, facial dysmorphisms, and seizures. No neurofibromas were present. Three sets of parents were tested: one duplication was apparently de novo, one inherited from an affected mother, and one inherited from a clinically normal father.conclusion: This is the first report comparing the phenotypes of nonrelated individuals with NF1 microduplications. This comparison will allow for further definition of this emerging microduplication syndrome.Genet Med 2012:14(5):508-514

Duplications, deletions, and single-nucleotide variations: the complexity of genetic arithmetic

“…The work of Moles et al 7 demonstrates that, when we define diseases on the basis of genomic etiology, the ultimate phenotypic spectrum is greater than that anticipated from the sum of the original cases' clinical findings. As we ascertain cases based on genotype (increasingly common in a genomic era), the expansion and redefinition of phenotypes will likely be a salient feature of clinical genetics.…”

“…Moles et al 7 describe seven individuals with a rare duplication CNV and a clinical problem that brought them to their physician. The physician's clinical judgment prompted diagnostic testing.…”

“…5 Detailed clinical, cell biology, and genomic data are now readily available on many patients with one of three NF1 microdeletion disorders, one of which usually involves mosaicism, indicating both meiotic and postzygotic mitotic origins of the deletions. These microdeletion cases and recently reported microduplication cases 6,7 are now poised to teach us something. In the May 2012 issue of Genetics in Medicine, Moles et al 7 reported rigorous genomic data on seven patients with "microduplications" of that portion of chromosome band 17q11.2, which, when deleted, accounts for several percent of patients specified to have the disorder NF1.…”

“…From March 2004 through April 2011, Moles et al 7 performed microarray analysis on 48,817 individuals, most often with a clinical indication of "intellectual disability, developmental delay, or multiple congenital anomalies. " The yield was one NF1 microduplication per 6,974 specimens per year.…”

“…The article by Moles et al 7 is relevant to NF1 in particular and genetic/genomic pathogenesis in general, precisely because this variation assumption has proved to be wrong. Specifically, NF1 results not only from many types of inherited and spontaneous intragenic mutations but also from relatively frequent somatic mosaicism and at least three different types of microdeletion syndromes.…”