Background: The renal cysts and diabetes (RCAD) syndrome caused by defects in the HNF1B is characterized by a broad spectrum of clinical features. While heterozygous point mutations are relatively rare, we focused on gross deletions of the HNF1B that are determined by multiplex ligation probe-dependent amplification (MLPA). Rather importantly, the deletions most often extend beyond the single HNF1B, thus more deleted genes may participate in the clinical picture.
Method: We compared the clinical phenotype of 13 patients (six males, median age 15.5 years) carrying the gross deletions whose extent was precisely determined by array comparative genomic hybridisation (aCGH) on CytoChip Oligo 8x60K with five patients (one male, median age 15.5 years) having point mutations in the HNF1B.
Results: The average length of heterozygous deletion was 1.69 Mb. The longest deletion reached 2.5 Mb affecting 47 genes and the shortest deletion found in three patients was 1.4 Mb long and deleted 16 genes including LHX1. Patients having longest deletions (2.5 and 2.1 Mb) manifested renal dysfunction at older age (10 and 30 years) with milder changes of the kidney structure (isolated cysts and functional changes only) and both presented diabetes as a first clinical feature. Patients with shorter deletion manifested renal changes (cystic kidney disease) prenatally and are mostly without diabetes. Comparing deletion and point mutation carriers, prenatal ultrasound kidney changes were found in 10/13 and 4/5 patients respectively. Diabetes manifested at the median age of 17 years in 5/13 and 2/5 patients. Hypomagnesaemia was present in 11/13 and 2/5 patients.
Conclusion: Although the dominating clinical phenotype of the patients with whole HNF1B deletion is similar with those having point mutations, the length of the deletion can contribute to the individual variability in the age of manifestation and other variability of the phenotype.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology