A girl with neurofibromatosis type 1, atypical autism and mosaic ring chromosome 17

Abstract

We describe a girl with neurofibromatosis type 1 (NF1), mild dysmorphic features, growth and mental retardation, autism, and mosaicism of ring chromosome 17 and chromosome 17 monosomy. The extent of genetic material deleted from the ring chromosome was determined using a combination of classical cytogenetics, fluorescence in situ hybridization (FISH) and multiplex ligation‐dependent probe amplification (MLPA) to be 0.6–2.5 Mb on 17p, and up to about 10 Mb on 17q. Based on our observations and on a review of the literature we argue that in addition to a universal “ring syndrome” which is based on ring instability and is less specific for the chromosome involved, various ring chromosomes underlie their own characteristic phenotypes. We propose that the symptoms leading to the diagnosis of NF1 in our patient could be attributed to mosaic hemizygosity for the NF1 gene in some of her somatic cells. A similar mechanism or a direct involvement of respective disease genes in the aberration could possibly influence also the development of autism and other symptoms. We raise a question if the loss of one copy of chromosome 17 from a substantial fraction of somatic cells can have specific consequences also for future risks of the patient, for example, due to the mosaic hemizygosity for the BRCA1 and TP53 genes. © 2006 Wiley‐Liss, Inc.

Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation

“…It has been hypothesised that the phenotypic abnormalities in this type of ring chromosome are due essentially to what is called “dynamic mosaicism” with pre- and postnatal growth retardation and microcephaly as consistent features 2 14. Several examples show the presence of specific phenotypes otherwise typically associated with dominant gene mutations in patients carrying ring chromosomes not deleted for the responsible genes 15 16. Thus, hemizygosity of the responsible gene(s) in a significant proportion of somatic cells due to the ring instability may explain the phenotype.…”

Mild ring 17 syndrome shares common phenotypic features irrespective of the chromosomal breakpoints location

“…The investigation of the p and q subtelomeric regions of ring chromosomes 17 is particularly relevant for disclosing candidate genes potentially involved in the phenotypic features associated with this cytogenetic abnormality. However, only one case was described at the molecular level (5, 6). Here, we describe the detailed molecular cytogenetic characterization of a non‐supernumerary ring chromosome 17 in a child with neurological disorders.…”

Molecular cloning and analysis of breakpoints on ring chromosome 17 in a patient with autism

“…The symptoms could also be influenced by her mosaic chromosome 17 monosomy (12% in blood lymphocytes). We are convinced that the mosaic monosomy was responsible for the symptoms of neurofibromatosis (the NF1 gene is not deleted from the ring chromosome 17), as well as for her potentially increased cancer risk due to mosaic hemizygosity of the TP53 and BRCA1 genes (Havlovicova et al, 2007). Nevertheless, the attributes of several of the deleted genes could make them candidates for the involvement in the symptoms observed in our patient including autism.…”

“…A detailed description of the patient was published previously (Havlovicova et al, 2007). Briefly, the girl had growth retardation, microcephaly, mild facial dysmorphism, scoliosis, café-au-lait spots, inguinal freckling and leukoderma.…”

“…We have previously described a girl with autism, mental retardation, mild dysmorphic features and neurofibromatosis, and a mosaic of non-supranumerary ring chromosome 17 and chromosome 17 monosomy (monosomy in 12% of peripheral blood lymphocytes) (Havlovicova et al, 2007). The breakpoints on both chromosome 17 arms were mapped to intervals between 0.6 and 2.5 Mb from the 17p telomere and between 0.7 and 10 Mb from the 17q telomere using a combination of classical cytogenetics, FISH and MLPA.…”