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A novel microdeletion / microduplication syndrome of 19p13.13

2010-08-01 21:52:20

Genetics in Medicine; 2010 Aug; 12(8):503-11


Michelle Dolan, Nancy J Mendelsohn, Mary Ella Pierpont, Lisa A Schimmenti, Susan A Berry, and Betsy Hirsch



Abstract



PURPOSE:



Whole genome interrogation by array-based comparative genomic hybridization has led to a rapidly increasing number of discoveries of novel microdeletion and/or microduplication syndromes. We here describe the clinical and cytogenomic correlates of a novel microdeletion/microduplication of 19p13.13.



METHODS:



Among patients referred to the Cytogenetics laboratory for array-based comparative genomic hybridization analysis, we identified four with a deletion and one with a duplication within 19p13.13. Confirmatory fluorescence in situ hybridization and parental studies were performed. Detailed clinical findings and array profiles were reviewed and compared.



RESULTS:



Patients with deletions of 19p13.13 share a unique constellation of phenotypic abnormalities. In addition to developmental disabilities, the microdeletion manifested in overgrowth, macrocephaly, and ophthalmologic and gastrointestinal findings; in contrast, the single microduplication manifested in growth delay and microcephaly.



CONCLUSION:



The consistent constellation of clinical findings associated with copy number variation of this region warrants the designation of microdeletion/microduplication syndrome of 19p13.13. An approximately 311-340 Kb smallest region of overlap encompassing 16 genes was identified. Candidate genes include MAST1, NFIX, and CALR. Identification of this syndrome has led to recommendations for diagnostic work-up and follow-up of patients with this copy number variant. Integration of detailed clinical and array data is critical for advancing both patient care and human genomic research.



Introduction



The incorporation of microarray technology into the routine assessment of patients with unexplained developmental disabilities and/or phenotypic abnormalities has resulted in the rapid discovery of numerous recurrent microdeletions/microduplications. For example, over a period of only 2 years, previously undetected losses and/or gains for the genomic regions of 1q21.11,2 and 16p11.23,4 have become widely recognized as potential etiologic factors for autism and related disorders. Copy number variants (CNVs) of clinical significance that involve too small a chromosomal region to be detected by conventional cytogenetics have
been identified for every chromosome pair in the human karyotype. For some CNVs, variability in expression and penetrance of clinical manifestations has complicated the establishment of clinical significance. For others, documenting clinical relevance has been facilitated by association of the CNV with more consistent and specific phenotypic findings, and with de novo inheritance. We here describe a CNV for chromosome 19p13.13 that meets the latter criteria. Despite the fact that chromosome 19 is one of the most gene-rich chromosomes (~2000 genes within 59Mb), to date, there have been only a few published reports of individuals with deletions involving 19p.5–10 Critical to identifying this microdeletion/microduplication syndrome was the consensus characterization of the clinical findings by four clinical geneticists and correlation of those findings with the microarray data.



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