The Bilginturan syndrome is caused by multiple rearrangements on chromosome 12p
The aim of our study is to identify the molecular basis of autosomal-dominant hypertension, brachydactyly type E, and short stature (Bilginturan syndrome; OMIM %112410). The hypertension resembles non-salt-sensitive primary hypertension in the general population. Untreated affected individuals die of stroke at age <50 years. The gene(s) reside on a 3.15 Mb, chromosome 12p region. We sequenced all known and predicted protein-coding genes to no avail. However, interphase fluorescence-in-situ-hybridization (iFISH) studies, using a five-clone BAC array spread across the locus, showed an inversion, deletion, and reinsertion mutation in lymphoblastoid cell lines in the original Turkish family. We now extended iFISH-analysis to three other families and one sporadic case (all non-Turkish), with a 24-clone, contiguous BAC array. We confirmed complex rearrangements at chromosome 12p. Surprisingly, all affected persons had an inversion of the centromeric part of the locus with a shared region. However, there were no common breakpoints and no disruptions of any known coding sequences. The sporadic case also had a partial deletion of the inverted sequence that was reinserted in the telomeric part of the locus. We conclude that chromosome 12p rearrangements are responsible for the hypertension-brachydactyly syndrome. Possible causes remain unknown genes or non-coding RNA. A position effect must also be considered that could alter the interplay between a regulatory element and its respective gene.