Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services.

Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105 K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4 years (2009-2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.

The Pathogenic Mechanisms and Therapeutic Strategies of Hutchinson-Gilford Progeria Syndrome / 生物化学与生物物理进展

Hutchinson-Gilford progeria syndrome (HGPS) is an early onset severe premature aging disorder due to a point mutation in LMNA gene which encodes nuclear lamin A/C. The mutation activates a cryptic splice site within exon 11 of LMNA, resulting in a 50-amino acid in-frame deletion in prelamin A. However, it is not clear how the mutation in a structural protein under the nuclear envelope could give rise to premature aging phenotypes. Recent studies showed that various abnormalities have been found in nuclear structures and functions of HGPS cells, mainly including progerin accumulation and nuclear morphology abnormalities, altered nuclear mechanical properties, changes of histone methylation patterns and epigenetic control, gene misregulation, p53 signalling activation, and increased genomic instability. Two hypotheses recently emerged in the explanation of the pathogenic mechanisms contributing to HGPS. No effective clinical intervention has been developed so far for HGPS. Several fascinating therapeutic strategies have recently been provided, such as farnesyltransferase inhibitors, antisense oligonucleotides and RNA interference. HGPS has been considered to be a model for studying the mechanisms responsible for normal aging. This study will help to elucidate the physiological functions of lamin A and nuclear envelope, together with their roles in normal aging process and diseases.