Diabet. Med. 27, 1454–1458 (2010) Abstract Objective We have dissected the rare molecular anomalies that may affect hepatocyte nuclear factor-1α (HNF1A) and hepatocyte nuclear factor-4α (HNF4A) in patients with familial young-onset diabetes for whom HNF1A mutations have been excluded by sequence analysis. Methods Eighty-four unrelated HNF1A-negative patients with diabetes diagnosed before the age of 40 years, a family history of diabetes and the absence of features suggestive of Type 2 diabetes were included. We analysed by sequencing the HNF4A promoter and coding regions, the HNF1A promoter region and specific regions of HNF1A(B) and HNF1A(C) isoforms and searched for large deletions of HNF1A and HNF4A by multiplex ligation-dependent probe amplification (MLPA). Results We identified five novel HNF4A mutations (5/84, 6%), including four missense and one in-frame deletion, and one mutation of the HNF1A promoter (1/84). Sequence analysis of isoform-specific coding regions of HNF1A did not reveal any mutation. We next identified two whole gene deletions of HNF1A and HNF4A, respectively (2/84, 2.4%). Conclusions Altogether, the search for rare molecular events in HNF1A and HNF4A led us to elucidate 8/84 (9.5%) of our HNF1A-negative cases. This study shows that genetic aetiologies remain to be elucidated in familial young-onset diabetes. It also highlights the difficulty of the differential diagnosis with Type 2 diabetes because of the wide clinical expression of monogenic young-onset diabetes and the absence of specific biomarkers.
