SNP array mapping of chromosome 20p deletions: Genotypes, phenotypes, and copy number variation

Abstract

The use of array technology to define chromosome deletions and duplications is bringing us closer to establishing a genotype/phenotype map of genomic copy number alterations. We studied 21 patients and 5 relatives with deletions of the short arm of chromosome 20 using the Illumina HumanHap550 SNP array to 1) more accurately determine the deletion sizes, 2) identify and compare breakpoints, 3) establish genotype/phenotype correlations and 4) investigate the use of the HumanHap550 platform for analysis of chromosome deletions. Deletions ranged from 95kb to 14.62Mb, and all of the breakpoints were unique. Eleven patients had deletions between 95kb and 4Mb and these individuals had normal development, with no anomalies outside of those associated with Alagille syndrome. The proximal and distal boundaries of these eleven deletions constitute a 5.4MB region, and we propose that haploinsufficiency for only 1 of the 12 genes in this region causes phenotypic abnormalities. This defines the JAG1 associated critical region, in which deletions do not confer findings other than those associated with Alagille syndrome. The other 10 patients had deletions between 3.28Mb and 14.62Mb, which extended outside the critical region, and notably, all of these patients, had developmental delay. This group had other findings such as autism, scoliosis and bifid uvula. We identified 47 additional polymorphic genome-wide copy number variants (>20 SNPs), with 0-5 variants called per patient. Deletions of the short arm of chromosome 20 are associated with relatively mild and limited clinical anomalies. The use of SNP arrays provides accurate high-resolution definition of genomic abnormalities.

A systematic analysis of small supernumerary marker chromosomes using array CGH exposes unexpected complexity

“…42 The deletion in our patient (chr20:9,493,095-12,089,631) falls within this cohort of deletions with a phenotype corresponding to Alagille syndrome.…”

Alagille syndrome in a Vietnamese cohort: Mutation analysis and assessment of facial features

“…All mutations were numbered based on the cDNA reference sequence, with position +1 corresponding to the A of the ATG translation initiation codon. If no mutations in JAG1 were detected, large deletion screening was performed using either a single-nucleotide polymorphism (SNP) array or multiplex ligationdependent probe amplification (MLPA) to detect exonic deletions as previously described [Kamath et al, 2009; Cho et al, 2009]. SNP array analysis was carried out using the Illumina Infinium SNP genotyping platform (HumanHap610 chips, BeadStation Scanner, and BeadStudio analysis software).…”

Alagille syndrome: pathogenesis, diagnosis and management

“…However, larger deletions are likely to be associated with additional problems such as learning difficulties. 44 The occasional finding of a cytogenetically visible deletion or rearrangement involving 20p12 was significant in allocating the ALGS locus to this region, 9,45 and the similarity of the phenotype between deletion and mutation cases suggests that haploinsufficiency is the mutational mechanism. Approximately 60% of mutations are de novo, and germline mosaicism may occur at a frequency up to 8%, 46 which must not be overlooked in genetic counselling, where appropriate.…”