Maturity Onset Diabetes of the Young (MODY) 5, also known as renal cysts and diabetes syndrome, is a rare autosomal dominant form of monogenic diabetes caused by mutations in the HNF1B gene encoding hepatocyte nuclear factor 1 homeobox beta. Whole gene deletions of one copy of HNF1B are the most common mutation underlying MODY5, with more extensive deletions encompassing HNF1B and several surrounding genes, known as 17q12 deletion syndrome, present in a sub-set of individuals with MODY5, who present with additional clinical features. Historically, these large scale deletions are not identified using Sanger or targeted next generation sequencing (NGS) panels, and require other tools, such as microarray-based genomic hybridization or multiplex ligation probe amplification to detect. Incorporating such tests to targeted sequencing adds significantly to cost and labor.

Recent advances in bioinformatics allow for identification of large-scale copy number variation (CNV) from NGS output data without requiring additional laboratory methods. The NGS data from 57 patients suspected to have MODY by their physicians but who were negative for pathogenic mutations using a targeted NGS approach were thus re-examined using a CNV calling tool (CNV Caller, VarSeq v1.4.3).

Three unrelated patients were found to have large scale deletions spanning HNF1B. These deletions were verified using whole exome sequencing data as well as microarray analysis (CytoScan, Affymetrix), which confirmed the presence of 17q12 deletion in all three individuals. The deletions varied in size from 1.46 to 1.85 million base pairs. Clinical correlation revealed a history of genitourinary abnormalities in all three probands.

These results confirm the utility of the CNV Caller tool in identifying large-scale deletions causing MODY5, as well as 17q12 deletion syndrome. This may represent an easier, more cost-effective approach to making this diagnosis, ultimately improving case detection and allowing for more personalized care for affected individuals.


A.J. Berberich: None. J. Wang: None. H. Cao: None. A.D. McIntyre: None. J.F. Robinson: None. P. Yang: None. J. Knoll: Stock/Shareholder; Self; Cytognomix Inc. R. Hegele: Consultant; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Amgen Inc., Regeneron Pharmaceuticals, Sanofi.

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