Increased ALK1 copy number and renal cell carcinoma-a case report.

There have been recent reports of a rare variant of renal cell carcinoma associated with upregulation of the anaplastic lymphoma kinase gene (ALK) arising as a consequence of chromosomal translocations. The tumours were described as having a characteristic morphology. Here, we describe a case with similar morphology characterised by eosinophilic cells, abundant intracytoplasmic lumina and scattered large ganglion-like tumour cells. There was focal staining for ALK demonstrated by immunohistochemistry. However, rather than exhibiting a chromosomal translocation involving ALK, the use of FISH and a break-apart probe demonstrated that there was increased copy number of intact 2p23, the chromosomal region containing the ALK gene. Furthermore, the use of comparative genomic hybridisation showed increase of the whole of chromosome 2 along with chromosomes 6 and 17. There was no evidence of loss of 3p nor of trisomy of 7 associated with clear cell and papillary carcinoma, respectively. We suggest that this demonstrates a novel mechanism of upregulation of ALK activity by increased copy number occurring during the development of a renal carcinoma with the characteristic ALK-associated morphology.

Interstitial microduplication of Xp22.31: Causative of intellectual disability or benign copy number variant?

The use of comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays has dramatically altered the approach to identification of genetic alterations that can explain intellectual disability and /or congenital anomalies. However, the discovery of numerous copy number changes with benign or unknown clinical significance has made interpretation problematic. Submicroscopic duplication of Xp22.31 has been reported as either a possible cause of intellectual disability and/or developmental delay or a benign variant. Here we report 29 individuals with the microduplication found as part of microarray analysis of 7793 samples submitted to an international group of 13 clinical laboratories. The referral reasons varied and included developmental delay, intellectual disability, autism, dysmorphic features and/or multiple congenital anomalies. The size of the Xp22.31 duplication varied between 149 kb and 1.74 Mb and included the steroid sulfatase (STS) gene with the male to female ratio of 0.7. Duplication within this segment is seen at a frequency of 0.15% in a healthy control population, whereas a frequency of 0.37% was observed in our cohort of individuals with abnormal phenotypes. We present a detailed comparison of the breakpoints, inheritance, X-inactivation and clinical phenotype in our cohort and a review of the literature for a total of 41 patients. To date, this report is the largest compilation of clinical and array data regarding the microduplication of Xp22.31 and will serve to broaden the knowledge of regions involving copy number variation (CNV).