Abstract
BackgroundJacobsen syndrome is a rare contiguous gene disorder that results from a terminal deletion of the long arm of chromosome 11. It is typically characterized by intellectual disability, a variety of physical anomalies and a distinctive facial appearance. The 11q deletion has traditionally been identified by routine chromosome analysis. Array-based comparative genomic hybridization (array-CGH) has offered new opportunities to identify and refine chromosomal abnormalities in regions known to be associated with clinical syndromes.ResultsUsing the 1 Mb BAC array (Spectral Genomics), we screened 70 chromosomally normal children with idiopathic intellectual disability (ID) and congenital abnormalities, and identified five cases with submicroscopic abnormalities believed to contribute to their phenotypes. Here, we provide detailed molecular cytogenetic descriptions and clinical presentation of two unrelated subjects with de novo submicroscopic deletions within chromosome bands 11q24-25. In subject 1 the chromosome rearrangement consisted of a 6.18 Mb deletion (from 128.25–134.43 Mb) and an adjacent 5.04 Mb duplication (from 123.15–128.19 Mb), while in subject 2, a 4.74 Mb interstitial deletion was found (from 124.29–129.03 Mb). Higher resolution array analysis (385 K Nimblegen) was used to refine all breakpoints. Deletions of the 11q24-25 region are known to be associated with Jacobsen syndrome (JBS: OMIM 147791). However, neither of the subjects had the typical features of JBS (trigonocephaly, platelet disorder, heart abnormalities). Both subjects had ID, dysmorphic features and additional phenotypic abnormalities: subject 1 had a kidney abnormality, bilateral preauricular pits, pectus excavatum, mild to moderate conductive hearing loss and behavioral concerns; subject 2 had macrocephaly, an abnormal MRI with delayed myelination, fifth finger shortening and squaring of all fingertips, and sensorineural hearing loss.ConclusionTwo individuals with ID who did not have the typical clinical features of Jacobsen syndrome were found to have deletions within the JBS region at 11q24-25. Their rearrangements facilitate the refinement of the JBS critical region and suggest that a) deletion of at least 3 of the 4 platelet function critical genes (ETS-1, FLI-1 and NFRKB and JAM3) is necessary for thrombocytopenia; b) one of the critical regions for heart abnormalities (conotruncal heart defects) may lie within 129.03 – 130.6 Mb; c) deletions of KCNJ1 and ADAMTS15 may contribute to the renal anomalies in Jacobsen Syndrome; d) the critical region for MRI abnormalities involves a region from 124.6 – 129.03 Mb. Our results reiterate the benefits of array-CGH for description of new phenotype/genotype associations and refinement of previously established ones.
Highlights
Jacobsen syndrome is a rare contiguous gene disorder that results from a terminal deletion of the long arm of chromosome 11
We report here the clinical and molecular cytogenetic findings in two subjects with submicroscopic rearrangements involving the 11q24-25 Jacobsen syndrome (JBS) critical region, detected while screening 70 children with idiopathic intellectual disability (ID) and physical anomalies, using a whole-genome 1 Mb BAC array
These two individuals are of particular interest since their deletions lie within the region that is commonly deleted in patients with Jacobsen syndrome [16]
Summary
Jacobsen syndrome is a rare contiguous gene disorder that results from a terminal deletion of the long arm of chromosome 11. It is typically characterized by intellectual disability, a variety of physical anomalies and a distinctive facial appearance. Array-based comparative genomic hybridization (array-CGH) has offered new opportunities to identify and refine chromosomal abnormalities in regions known to be associated with clinical syndromes. Jacobsen syndrome (JBS: OMIM 147791) was one of the first recognised contiguous gene syndromes, resulting from a terminal deletion of the long arm of chromosome 11 [6]. Several other JBS deletion breakpoints in the 11q23.3-qter region were shown to localize to CCG repeat expansions [10]. Several studies have provided a genotype-phenotype correlation in an attempt to identify critical regions for the most common physical abnormalities seen in Jacobsen syndrome [7,8]
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